WO1996039126A2

WO1996039126A2 - Ranitidine salts on magnesium trisilicate as an adsorbate

Info

Publication number: WO1996039126A2
Application number: PCT/US1996/008978
Authority: WO
Inventors: Albert F. Sorg; Kirti H. Valia; Anthony B. Eoga; John Denick, Jr.
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1995-06-06
Filing date: 1996-06-05
Publication date: 1996-12-12
Anticipated expiration: 1997-12-06
Also published as: AU6378796A; WO1996039126A3

Abstract

A ranitidine adsorbate on magnesium trisilicate for oral administration that is free from the bitter and unpleasant taste associated with ranitidine. The ranitidine in the adsorbate is present in a stable, amorphous form and is compatible with pharmaceutically acceptable excipients.

Description

TITLE

RANITIDINE SALTS ON MAGNESIUM TRISILICATE AS AN ADSORBATE

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to stable amorphous ranitidine salts on magnesium trisilicate as an adsorbate. In vitro dissociation of the ranitidine from the adsorbate is significant, the ranitidine adsorbate demonstrating a high dissolution rate and a high degree of solubility. The adsorbate is also characterized as masking the bitter, unpleasant taste of ranitidine. The present invention also relates to pharmaceutical compositions comprising stable amorphous ranitidine salts on magnesium trisilicate as an adsorbate. The compositions contain pharmaceutically acceptable excipients and the like. It has been unexpectedly discovered that when ranitidine is complexed with magnesium trisilicate, the ranitidine is stabilized even in the presence of otherwise incompatible excipients.

Description of the Background Art Ranitidine, N-[2-[[[5-(dimethylamino)methyl-2- furanyl]methyl]thio]ethyl]-N'-methyl-2-nitro- 1 , 1 -ethenediamine, and its physiologically acceptable salts are described and claimed in U.S. Patent No. 4,128,658. A particular crystalline form of ranitidine hydrochloride is described and claimed in U.S. Patent No. 4,521,431. Ranitidine is a potent histamine ^-antagonist, which, in the form of its hydrochloride salt, is widely used in treating conditions that benefit from the lowering of gastric acidity. Such conditions include duodenal and gastric ulceration, reflux esophagitis, Zollinger-Ellison syndrome, heartburn, and over-indulgence symptoms (e.g., acid and stomach, sour stomach and regurgitation). Ranitidine may also be used prophylactically in surgical procedures and in treating allergic and inflammatory conditions where histamine is a known mediator.

It is known and widely demonstrated that the dissolution rate and solubility of a ranitidine represents a determining factor in its therapeutic activity. It is known that its therapeutic activity depends on the bioavailability of the medicament, which is a function of good and/or complete absorption. The latter depends on the degree of dissolution of the ranitidine. The good dissolution of ranitidine is all the more indispensable as there exists a certain and very limited area of the gastrointestinal tract adapted to absorb the ranitidine and the non-availability of the drug following its poor or incomplete dissolution in contact with this area causes poor absorption and, thereby, a therapeutic action which ranges from reduced to very variable. For a long time attempts have been made to prepare medicaments containing ranitidine in amorphous form, of which form the solubility is equal to or higher than that of the crystalline form (see review of J. Haleblain, J. Pharm. Sci, 64, 1269 (1975)). However these amorphous forms present the problem that they are converted readily in time into crystalline forms, i.e., amorphous forms may not be physically stable, which is a very serious drawback for maintaining the enhanced dissolution of a substance for therapeutic use. It would be beneficial if a physically stable form of ranitidine were discovered that did not convert readily in time into a crystalline form. Ranitidine is also problematic because its preferred route for administration is oral. Ranitidine and its salts have an inherently bitter taste, which constitutes a disadvantage with certain types of oral preparation. Moreover, it is well known that patients may not complete a necessary course of medicine if they are prescribed an oral presentation which is particularly unpleasant to taste. The problems resulting from the bitter taste of ranitidine are particularly acute in formulations such as chewable tablets, granules, powders, solutions or suspensions. To some extent, the bitter taste may be masked by the use of sweetening and/or flavoring agents, although this is not entirely satisfactory, and an unpleasant after-taste may still remain in the mouth. In addition, there may be circumstances in which it is undesirable or inappropriate to use a sweetening and/or flavoring agent.

Various methods of taste-masking ranitidine have been described. For example, PCT Patent Publication No. 94/08560 discloses a chewable ranitidine tablet comprising ranitidine, a chewable base selected from sucrose, glucose, lactose, maltose, or a mixture thereof, a flavoring agent, and, optionally, an intense sweetener. U.S. Patent No. 5,219,563 describes complexes formed between ranitidine and an ion exchange resin to give a resin adsorbate that is substantially free of the bitter taste associated with ranitidine. PCT Patent Publication No. 94/08576 discloses coating ranitidine particles with a lipid to mask their bitter taste. PCT Patent

Publication No. 94/20074 discloses a good-tasting, adsorbate composition comprising ranitidine, magnesium aluminum silicate, magnesium trisilicate and optionally additional pharmaceutically acceptable active ingredients. PCT Patent Publication No. 95/05173 discloses chewable tablets of ranitidine that are prepared using calcium carbonate and a supportive magnesium aluminum silicate.

Ranitidine is further problematic because of its incompatibility with certain pharmaceutically acceptable excipients and its instability due to processing conditions. Degradation products have been discovered in pharmaceutical compositions comprising ranitidine. Excipients such as sodium benzoate, sodium lauryl sulfate and starch, and processing conditions such as high temperatures, pH and water levels, produce detectable levels of the degradation product, ranitidine-s-oxide.

It can be understood that it would be advantageous to provide a taste-masked, amoφhous form of ranitidine with a high degree of solubility and dissolution, while preserving its physical and chemical stability. The present inventors have now discovered that a stable amoφhous form of ranitidine may be unexpectedly formed via novel and unobvious techniques by preparing an adsorbate comprising magnesium trisilicate and ranitidine. The present inventors have also discovered that the bitter and unpleasant taste of ranitidine may be unexpectedly masked by forming an adsorbate comprising magnesium trisilicate and ranitidine. Further, the ranitidine adsorbate can be processed into a stable pharmaceutical composition which is compatible with well-known excipients.

SUMMARY OF THE INVENTION

The present invention provides a ranitidine adsorbate for oral administration that is in a stable amoφhous state. The present invention also provides a ranitidine adsorbate for oral administration that is free from the bitter and unpleasant taste associated with ranitidine while maintaining acceptable levels of drug activity.

More particularly, the present invention provides a stable amoφhous and taste-masked ranitidine adsorbate which comprises magnesium trisilicate containing adsorbed therein ranitidine or a physiologically acceptable salt thereof. The ranitidine adsorbate is compatible with well-known pharmaceutically acceptable excipients and can be used to prepare stable pharmaceutical compositions. Compatible excipients are, for example, starch, kaolin, calcium phosphate, talc, calcium carbonate, lactose, saccharose carboxymethylcellulose, sodium alginate, methylcellulose, dextrin, glucose and the like. Apart from the foregoing features, the invention also comprises other features which will emerge from the description which follows. The present invention will best be understood by means of the additional description which follows, in which examples of the preparation of novel medicaments according to the present invention are given, as well as the characteristics of the products obtained. Numerous analyses, and particularly powder X-ray diffractometry carried out by the inventors have enabled it to be envisaged that the ranitidine in the adsorbate complex is in the form of an amoφhous drug.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a wet granulation method.

Figure 2 is an X-ray diffraction pattern of heated ranitidine adsorbate prepared by a wet granulation method.

Figure 3 is an X-ray diffraction pattern of ranitidine HCI. Figure 4 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a spray-dried method.

Figure 5 is an X-ray diffraction pattern of ranitidine adsorbate prepared with maltodextrin by a spray-dried method.

Figure 6 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a wet granulation method.

Figure 7 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a wet granulation method. , Figure 8 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a wet granulation method.

Figure 9 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a wet granulation method.

Figure 10 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a wet granulation method. Figure 11 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a wet granulation method.

Figure 12 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a spray-dried method. Figure 13 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a spray dried method.

Figure 14 is an X-ray diffraction pattern of ranitidine adsorbate prepared by a spray-dried method.

Figure 15 is a Differential Scanning Calorimetry analysis of ranitidine HCI and citric acid.

Figure 16 is a Differential Scanning Calorimetry analysis of ranitidine HCI and malic acid.

Figure 17 is a Differential Scanning Calorimetry analysis of . ranitidine adsorbate and citric acid. Figure 18 is a Differential Scanning Calorimetry analysis of ranitidine adsorbate and malic acid.

DETAILED DESCRIPTION OF THE INVENTION Ranitidine may be employed in forming the adsorbate according to the present invention in the form of either its free base or a physiologically acceptable salt. Such salts include salts with inorganic or organic acids such as the hydrochloride, hydrobromide, sulphate, acetate, maleate, succinate, fumarate, citrate, tartrate and ascorbate salts. A particularly preferred salt for use according to the invention is the hydrochloride salt.

Magnesium trisilicate is a fine, white, odorless powder. The term magnesium trisilicate does not have a precise description but approximates the formula 2Mgθ3Siθ2-xH2θ. The physical texture and adsoφtive properties of magnesium silicates have been varied depending predominately upon their mode of preparation. These materials, however, generally possess a water content of 5% to 34%, a minimum of 20% magnesium oxide, a minimum of 45% silicon dioxide, and a ratio of MgO to Si0₂ of about 2.10 to about 2.30.

The method of making the magnesium trisilicates used in this invention is not critical and is not considered a part of this invention. The magnesium trisilicates employed as the ranitidine substrate in the present invention are well-known materials which are believed to occur naturally. Alternatively, they may be prepared by methods well-known to those of ordinary skill in the art. Such methods, as taught, for example, in U.S. Patent No. 3,272,594, generally involve reacting an alkali metal silicate such as sodium silicate with a magnesium salt such as magnesium sulfate under heat. The magnesium trisilicate is then precipitated and recovered. The particular magnesium trisilicate employed in the present invention, and its method of preparation, are not critical. Any conventional magnesium trisilicate may be employed as long as it is capable of adsorbing ranitidine.

The preferred magnesium trisilicates are described in U.S. Patent No. 4,642,231. They have a surface area of at least 400 m /g, preferably from at least 400 πr7g to about 1000 m /g, and most preferably from about 440 m 2 /g to about 600 m 2 /g, and also have a flake-like structure with multiple interstitial spaces. The disclosure of U.S. Patent No.

4,642,231 is hereby incoφorated by reference.

While the invention is not to be limited to theoretical considerations, it is believed that the magnesium trisilicate surface area and its flaked-like surface provide its unusual ability to adsorb ranitidine within the channels, convolutions or interstitial spaces of the adsorbate. Once adsorbed within the magnesium trisilicate, it is believed that the ranitidine is not available for organoleptic taste prior to passage into the digestive tract and subsequent desoφtion by the gastric juices.

The ranitidine adsorbate of the invention can be prepared by any known processes, such as granulation or slurry techniques. The granulation or slurry techniques involve the initial step of dissolving the ranitidine or its physiologically acceptable salt in a suitable inert solvent and then mixing the resulting solution with the magnesium trisilicate to obtain a homogeneous dispersion. The solvent concentration of that dispersion may vary widely but generally ranges from about 15% to about 60% by weight, based on the weight of the total composition. When mixing is performed with lower amounts of solvent, for example, 15% to about 35% by weight of the total composition, the resulting mixture is dried to a predetermined moisture content between 5% and 20% by weight of the final composition and milled to obtain a granulated product. When higher solvent concentrations are employed, a slurry is formed containing ranitidine or its physiologically acceptable salt and magnesium trisilicate. The solvent is then removed and the adsorbate is recovered and used as a paste or dried to a free flowing powder. Solvent concentrations may range from about 5% to about 60% by weight of the total composition for optimum results.

Any solvent may be used to prepare the adsorbate of this invention provided that it is capable of dissolving ranitidine. Representative solvents include water; polyhalogenated lower hydrocarbons such as chloroform, methylene chloride; lower alcohols, such as methanol, ethanol, propanol and butanol; ketones such as acetone; ethers; and aromatic solvents; and mixtures thereof; with water being the preferred solvent.

In one embodiment, the ranitidine may be combined with one or more medicament drugs and dissolved in the solvent. The medicament drugs may be selected from a wide variety of drugs and their acid addition salts. Suitable categories of drugs that may be employed along with ranitidine in the instant adsorbate may vary widely and generally represent any stable adsorbate drug combination. Illustrative categories and specific examples include: a) antitussives, such as dextromethoφhan, dextromethoφhan hvdrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride; b) antihistamines, such as chloφheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine and triprolidine; c) decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine; d) various alkaloids, such as codeine phosphate, codeine sulfate and moφhine; e) anti-ulcer products including H_j- and H2- antagonists as well as proton pump inhibitors. H_j- antagonists include ethanolamine derivatives (e.g. diphenhydramine), ethylenediamine derivatives

(tripelennamine), alkylamine derivatives (chloφheniramine maleate), piperazine derivatives, phenothiazine derivatives (promethazine). H2- antagonists include cimetidine, famotidine, and nizatidine, while homeprasole should be in particular quoted among proton pump inhibitors. Anti-ulcer products are also inclusive of prostaglandins, carbenoxolane and sucralphate. A comprehensive class of pharmaceuticals that can be conveniently used according to the invention is that of cardiovasculars. The said class includes diuretics (e.g. chlorothiazide), peripheral vasodilators (e.g. hydralazine), coronary vasodilators (isosorbide, nitroglycerin), beta-blockers (metopropol), anticholersteraemic agents (e.g. clofibrate); f) antiarrhythmic drugs, e.g. verapamil, propranolol, phenytoin, procainamide, amiodarone, quinidine; g) antihypertensive drugs are also covered by the invention. For instance, renin-angiotensin system inhibitors, such as ACE-inhibitors, result to be particularly interesting (e.g. captopril, enalapril); h) calcium antagonists, such as nifedipine, verapamil, diltiazem, are among the best suited groups of formulations covered by the invention, just as beta-blockers, whether a specific (propranolol, nadolol, timolol, pindolol) or cardioselective (metoprolol); i) antiasthmatic drugs, β2-adrenergics, e.g. salbutamol (albuterol), terbutaline, carbuterol, broxaterol, aminophylline, theophylline; j) antiemetic and antinauseant drugs (cyclizine, cinnarazine, domperidone, alizapride); k) anticancer drugs, whether for topical action on gastrointestinal tumours or for systemic action, such as vincristine, steroid derivatives like medroxyprogesterone acetate and megestrol acetate, antibiotics, e.g. vincristine, steroid derivatives like medroxyprogesterone acetate and megestrol acetate, antibiotics, e.g. daunorubicin, actinomycin, adriamycin, epipodophyllotoxins, e.g. etoposide and teniposide, antimetobolites, e.g. 5- fluorouracil;

1) non-steroid antiinflammatory drugs (NSAID), such as acetylsalicylic acid, indomethacin, acemethacin, sulindac, piroxicam, ibuprofen, naproxen, ketoprofen; m) central-action drugs, such as benzodiazepines (e.g. temazepam, lorazepam, flunitrazepam), antiparkinson agents (L-dopa, amantadine), tricyclic antidepressants (protriptyline hydrochloride, trimipramine maleate) and MAO-inhibitors (e.g. isocarboxazid), psychostimulants, antiepileptics; cerebral vasodilators such as nicergoline; and n) antimicrobial agents such as antibacterials, antiviral drugs, and fungicides such as penicillin derivatives (e.g. ampicillin, amoxycillin), aminoglycosides, cephalosporins (cefalzolam, ceftriaxone), macrolides (erythromycin), tetracyclines, antiviral drugs used in the treatment of heφes infections (acyclovir, gancyclovir), and the latest developed anti-AIDS agents (e.g. zidovudin or azidothymidine).

The concentration of ranitidine, or its physiologically acceptable salt, in the solution varies widely, but is generally from about 2% to about 6%. More preferably, the concentration of the ranitidine, or its physiologically acceptable salt, in the solution is from about 2.5% to about 5.9%. Most preferably, the amount of ranitidine, or its physiologically acceptable salt, in the solution is from about 2.8% to about 5.8.

The concentration of magnesium trisilicate in the solution containing ranitidine varies widely, but is generally from about 0.4% to about 31%.

In terms of milliequivalents amount of magnesium trisilicate added to neutralize the ranitidine in the solution, about 0.22 meqv to about 0.26 meqv of magnesium trisilicate is added to the solution, more preferably, about 0.238 meqv to about 0.24 meqv, and most preferably, about 0.239 meqv to about 0.241 meqv. Preferably, the concentration of the magnesium trisilicate in the solution will be controlled by the targetted ANC value of the final product. This amount will depend upon the initial ANC value of the raw material.

The magnesium trisilicate is added, preferably while stirring, to the medicament solution in more than one portion. Preferably, the magnesium trisilicate is added to the medicament solution in about 2 or more portions. More preferably, the magnesium trisilicate is added to the medicament solution in about 5 to about 15 portions. Most preferably, the magnesium trisilicate is added to the medicament solution in about 8 to about 12 portions.

The amount of the portions of magnesium trisilicate incrementally added to the medicament solution is in the range from about 5% to about 15% by weight of the total amount of magnesium trisilicate. Preferably, the amount of the portions of magnesium trisilicate incrementally added to the medicament solution is in the range from about 10% to about 12% by weight of the total amount of magnesium trisilicate. More preferably, the amount of the portions of magnesium trisilicate incrementally added to the medicament solution is in the range from about 10.5% to about 11.5% by weight of the total amount of magnesium trisilicate. Most preferably equal amounts of magnesium trisilicate are incrementally added to the medicament solution.

The time period after which a subsequent portion of magnesium trisilicate is incrementally added to the medicament solution is in the range from about 2 to about 5 minutes. Preferably, the time period is in the range from about 3 to about 4.5 minutes. More preferably, the time period is in the range from about 3.5 to about 4 minutes.

The temperature existing when the magnesium trisilicate is incrementally added to the medicament solution is in the range from about 15 to about 90°C. Preferably, the temperature is in the range from about 20 to about 32°C. More preferably, the temperature is room temperature.

In general, the temperature may be subject to great variation depending upon the medicament dissolved in the solvent.

As an example, while stirring at room temperature, an amount of magnesium trisilicate equal to the amount of a medicament dissolved in a solution is added to that solution. After one minute of stirring, a second amount of magnesium trisilicate equal to the amount of a medicament dissolved in the solution is added to the slurry while the mixture is continuously stirring. The latter procedure is then repeated until each portion of the magnesium trisilicate is introduced into the slurry. In one embodiment of the present invention, more than one type of adsorbate is incrementally added to the medicament solution. In other words, a second, or greater number of adsorbates, such as silicon dioxide, is added to the medicament solution. The additional adsorbate may supplement or replace an amount of the magnesium trisilicate otherwise added to the medicament solution. Thus, after one or more portions of magnesium trisilicate is incrementally added to the medicament solution, one or more portions of additional adsorbates are incrementally added to the medicament solution, in one embodiment, one or more portions of silicon dioxide are incrementally added to the medicament solution. The additional adsorbate may also be combined with the magnesium trisilicate and be incrementally added to the medicament solution.

The number of portions, and amounts of the additional adsorbates will vary. In general, the time period and temperature at which the additional adsorbates are added to the medicament solution are similar to the time period and temperature at which the magnesium trisilicate is added to the medicament solution. In one embodiment of the present invention, two portions of silicon dioxide in a total amount about equal to the amount of medicament in solution are incrementally added in one minute intervals at room temperature to the medicament solution after the magnesium trisilicate.

Another embodiment of the present invention, comprises the step of adding at least one coating ingredient to the magnesium trisilicate medicament mixture. Preferably, at least one coating ingredient is added to the magnesium trisilicate medicament mixture after all of the adsorbate is added to the medicament solution. Most preferably, while stirring and applying mild heat, a soluble coating ingredient is added to the magnesium trisilicate medicament mixture after all of the adsorbate is added to the medicament solution.

The step of addition of the coating agent is used to decrease any electrostatic forces between the adsorbate particles as they are being prepared. Coating ingredients are compounds which exert a strong physicochemical attractive force between molecules. Suitable coating ingredients in the present invention include maltodextrin corn syrup, polyvinyl pyrrolidine, acacia, gelatin, glucose, guar gum, pregelatinized starch and sodium alginate, and cellulose derivatives such as ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, . sodium carboxymethylcellulose, polyethylene oxide, sodium caseinate, polyvinyl alcohol, locust gum, and the like, and mixtures thereof. Preferably, the coating ingredient is maltodextrin. An effective amount of coating ingredient is added to the magnesium trisilicate medicament solution. An effective amount of coating ingredient is an amount which will allow a medicament adsorbate to be uniformly distributed. The amount of coating ingredient is a matter of preference, subject to such factors as the type of magnesium trisilicate or medicament, and type of coating ingredient employed. Thus, the amount of coating ingredient may be varied in order to obtain the result desired in the final product. In the preferred embodiment of the present invention, while stirring, one portion of maltodextrin, in an amount equal to about twice the amount of medicament in the mixture, is added to the magnesium trisilicate medicament mixture after all of the adsorbate is added to the medicament solution.

The addition of the coating ingredient to the magnesium trisilicate medicament solution to coat the medicament adsorbates after recovery is also advantageous to formulation. The addition of known medicament adsorbates to pharmaceutically inactive ingredients can lead to problems in terms of compatibility. Specifically, a large number of flavors and soluble acids cannot be combined with known medicament adsorbates without stability problems occurring as a result of incompatibility. Through the application of a coat, the medicament adsorbates of the present invention can be combined with heretofore incompatible agents. The coating ingredient minimizes the intimate contact between the medicament and pharmaceutically inactive excipients, soluble acids, flavors, etc. Also the coating allows the medicament adsorbates to be tailored to deliver controlled release of a medicament(s). After the addition of the soluble coating ingredient, the solution is stirred. Preferably, the solution is stirred for about 20 minutes.

The present invention further comprises the step of recovering the medicament adsorbate from the magnesium trisilicate medicament mixture. The recovery of the medicament adsorbate is achieved in one embodiment by conventional granulation and or slurry recovery techniques which are known to those of skill in the art. When a granulation approach is employed, and the mixture is prepared using low amounts of solvents, the resulting granulation product is removed and dried to a predetermined moisture content between 5% and 20% by weight of the final composition.

When higher solvent concentrations are employed and a slurry is formed, the solvent is removed and the adsorbate recovered and used as a paste or dried to a free flowing powder.

In another more preferred embodiment of the present invention, the medicament adsorbate is recovered from the magnesium trisilicate medicament mixture by a spray drying technique. Without removing the solvent, or by removing enough of the solvent so as to still allow, the magnesium trisilicate medicament mixture is spray dried by conventional techniques to a free flowing white powder. The ranitidine adsorbate thus prepared may be stored for future use or formulated with conventional pharmaceutically acceptable carriers to prepare medicated compositions which offer a variety of textures to suit particular applications. The compositions according to this invention may, for example, take the form of tablets, capsules, granules, powders, or lozenges, or liquid preparations such as suspensions. Granules and powders may be ingested directly, or dispersed in water or other suitable vehicle prior to administration. Capsules may be of the hard or soft gelatin type, including chewable soft gelatin capsules.

Chewable, suckable, or swallowable tablets (including cast chewable tablets), chewable soft gelatin capsules, granules, and aqueous or non- aqueous suspensions represent particular dosage forms, of which chewable or suckable tablets, granules, and aqueous or non-aqueous suspensions are particularly preferred.

The compositions may be formulated using conventional carriers or excipients and well established techniques. Without being limited thereto, such conventional carriers or excipients include diluents, binders and adhesives (i.e., cellulose derivatives and acrylic derivatives), lubricants (i.e., magnesium or calcium stearate, or vegetable oils, polyethylene glycols, talc, sodium lauryl sulphate, polyoxy ethylene monostearate), disintegrants, colorants, flavorings, preservatives, sweeteners and miscellaneous materials such as buffers and adsorbents in order to prepare a particular medicated composition. The preparation of confectionery and chewing gum products is historically well known and has changed very little over the years.

Thus, for example, granules for direct ingestion or for reconstitution before administration may be prepared by granulating the ranitidine adsorbate with a binding agent (e.g., polyvinylpyrrolidone or hydroxypropyl methylcellulose) and other suitable excipients such as fillers (e.g., sugars such as lactose, sucrose, dextrose, fructose, maltose and mannose, preferably fructose and mannose, or sugar alcohols such as sorbitol, xylitol and mannitol). The sugar alcohol fillers, e.g., mannitol, may affect the bioavailability of ranitidine. Tablets of the ranitidine adsorbate may be obtained by compressing the granules with suitable tabletting aids such as lubricants (e.g., magnesium stearate) and additional binder. Cast chewable tablets may be prepared by incoφorating the ranitidine adsorbate in one or more low melting point fatty base(s) (e.g., triglyceride bases). Capsules may be prepared by dispersing the ranitidine adsorbate in a suitable vehicle such as fractionated coconut oil and using standard equipment for the filling of soft and hard gelatin capsules.

Aqueous suspensions may be obtained by dispersing the ranitidine adsorbate in a suitable aqueous vehicle such as water or aqueous alcohol 17 (e.g., ethanol), optionally with the addition of suitable viscosity enhancing agent(s) (e.g., cellulose derivatives, xanthan gum, etc.). Non-aqueous suspensions may be obtained by dispersing the ranitidine adsorbate in a suitable non-aqueous based vehicle, optionally with the addition of suitable viscosity enhancing agent(s) (e.g., hydrogenated edible fats, aluminum stearate, etc.). Suitable non-aqueous vehicles include, for example, almond oil, arachis oil, soybean oil or fractionated vegetable oils such as fractionated coconut oil. Preservative(s) (e.g., methyl, ethyl, propyl or butyl-hydroxybenzoates, sodium benzoate or sorbic acid, etc.) may be included as appropriate.

Aqueous based suspensions of the ranitidine adsorbate may, if desired, be formed in situ by adding the magnesium trisilicate to a solution of ranitidine or a physiologically acceptable salt thereof in a suitable aqueous vehicle or, more preferably, by adding water to a dry mix of the magnesium trisilicate and the ranitidine or ranitidine salt in powder or granular form.

Lozenges are flavored medicated dosage forms intended to be sucked and held in the mouth. They may be in the form of various shapes, the most common being flat, circular, octagonal and biconvex forms. The lozenge bases are generally in two forms, hard, boiled candy lozenges and compressed tablet lozenges.

The hard boiled candy lozenges are prepared from a mixture of sugar and other carbohydrates that are kept in an amoφhous or glassy condition. This form can be considered a solid syrup of sugars generally having from 0.5 to 1.5%» moisture. Such materials normally contain up to 92% corn syrup, up to 55% sugar and from 0.1% to 5.0% water. The syrup component generally is prepared from corn syrups high in fructose, but may include other materials. Further ingredients such as flavorings, sweeteners, acidulents, colorants and so forth may also be added. In contrast, compressed tablet lozenges contain particular materials and are formed into structures under pressure. They generally contain sugars in amounts up to 95% and typical tablet excipients such as binders and lubricants as well as flavors, colorants and so forth.

The lozenges may be made of soft confectionery materials such as those contained in nougat. These materials contain two primary components, namely a high boiling syrup such as corn syrup or the like, and a relatively light textured frappe, generally prepared from gelatin, egg albumen, milk proteins such as casein, and vegetable proteins such as soy protein, and the like. The frappe is generally relatively light, and may, for example, range in density from about 0.5 to about 0.7g/cc.

By comparison, the high boiling syrup, or "bob syrup", is relatively viscous and possesses a higher density, and frequently contains a substantial amount of sugar. Conventionally, the final nougat composition is prepared by the addition of the "bob syrup" to the frappe under agitation, to form the basic nougat mixture. Further ingredients such as flavorings, oils, additional sugar and the like may be added thereafter also under agitation. A general discussion of the composition and preparation of nougat confections may be found in B.W. Minifie, CHOCOLATE, COCOA AND CONFECTIONERY: Science and Technology, 2nd edition, AVI Publishing Co., Inc., Westport, Connecticut, (1980), at Pages 424-425.

Pharmaceutical tablets of this invention may also be in the form of chewable forms. This form is particularly advantageous because of convenience and patient acceptance and rapid onset of bioactivity. To achieve acceptable stability and quality, as well as good taste and mouth feel, several considerations are important, namely the amount of active substance per tablet, flavor, compressibility and organoleptic properties of the drug.

The preparation of chewable medicated candy is prepared by procedures similar to those used to make soft confectionery. This procedure generally involves the formation of a boiled sugar-corn syrup blend to which is added a frappe mixture. The boiled sugar-corn syrup blend may be prepared from sugar and corn syrup blended in parts by weight ratio of 90 to 10 : 10 to 90. This blend is heated to temperatures above 250°F to remove water and to form a molten mass. The frappe is generally prepared from gelatin, egg albumen, milk proteins such as casein, and vegetable proteins such as soy protein, and the like which are added to a gelatin solution and rapidly mixed at ambient temperature to form an aerated sponge like mass. The frappe is then added to the molten candy base and mixed until homogenous at temperatures between 150°F and 250°F. The medicament adsorbate can then be added as the temperature of the mix is lowered to around 150°F to 200°F whereupon additional ingredients are added such as flavors, and colorants. The formulation is further cooled and formed to pieces of desired dimensions.

A general discussion of the lozenge and chewable tablet forms of confectionery may be found in H.A. Lieberman and L. Lachman,

Pharmaceutical Dosage Forms: Tablets Volume 1, Marcel Dekker, Inc., New York, N.Y. at pages 289 to 466.

With regard to the chewing gum formulation in particular, the amount of gum base employed will vary greatly depending on various factors such as the type of base used, consistency desired and other components used to make the final product. In general, amounts of about 5% to about 45% by weight of the final chewing gum composition are acceptable for use in chewing gum compositions with preferred amounts of about 15% to about 25% by weight. The gum base may be any water- insoluble gum base well known in the art. Illustrative examples of suitable polymers in gum bases include both natural and synthetic elastomers and rubbers. For example, those polymers which are suitable in gum bases, include, without limitation, substances of vegetable origin such as chicle, jelutong gutta percha and crown gum. Synthetic elastomers such as butadiene-styrene copolymers, isobutylene-isoprene copolymers, polyethylene, polyisobutylene and polyvinylacetate and mixtures thereof, are particularly useful.

The gum base composition may contain elastomer solvents to aid in softening the rubber component. Such elastomer solvents may comprise methyl, glycerol or pentaerythritol esters of rosins or modified rosins, such as hydrogenated, dimerized or polymerized rosins or mixtures thereof. Examples of elastomer solvents suitable for use herein include the pentaerythritol ester of partially hydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerol ester of wood rosin, glycerol ester of partially dimerized rosin, glycerol ester of polymerized rosin, glycerol ester of tall oil rosin, glycerol ester of wood rosin and partially hydrogenated wood rosin and partially hydrogenated methyl ester of rosin, such as polymers of alpha-pinene or beta-pinene; teφene resins including polyteφene and mixtures thereof. The solvent may be employed in an amount ranging from about 10% to about 75% and preferable about 45% to about 70% by weight to the gum base.

A variety of traditional ingredients such as plasticizers or softeners such as lanolin, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glycerine and the like for example, natural waxes, petroleum waxes, such as polyurethene waxes, paraffin waxes and microcrystalline waxes may also be incoφorated into the gum base to obtain a variety of desirable textures and consistency properties. These individual additional materials are generally employed in amounts of up to about 30% by weight and preferably in amounts of from about 3% to about 20% by weight of the final gum base composition.

The chewing gum composition may additionally include the conventional additives of flavoring agents, coloring agents such as titanium dioxide; emulsifiers such as lecithin and glyceryl monostearate; and additional fillers such as aluminum hydroxide, alumina, aluminum silicates, calcium carbonate, and talc and combinations thereof. These fillers may also be used in the gum base in various amounts. Preferably the amount of fillers when used will vary from about 4% to about 30% by weight of the final chewing gum.

In the instance where auxiliary sweeteners are utilized, the present invention contemplates the inclusion of those sweeteners well known in the art, including both natural and artificial sweeteners. Thus, additional sweeteners may be chosen from the following non-limiting list:

A. Water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol and mixtures thereof.

B. Water-soluble artificial sweeteners such as the soluble saccharin salts, i.e., sodium, or calcium saccharin salts, cyclamate salts, acesulfam-K and the like, and the free acid form of saccharin.

C. Dipeptide based sweeteners such as L-aspartyl- phenylalanine methyl ester and materials described in U.S. Patent No. 3,492,131 and the like.

In general, the amount of sweetener will vary with the desired amount of sweeteners selected for a particular chewing gum. This amount will normally be 0.001% to about 90% by weight when using an easily extractable sweetener. The water-soluble sweeteners described in category A above, are preferably used in amounts of about 25% to about 75% by weight, and most preferably from about 50% to about 65% by weight of the final chewing gum composition. In contrast, the artificial sweeteners described in categories B and C are used in amounts of about 0.005% to about 5.0% and most preferably about 0.05% to about 2.5% by weight of the final chewing gum composition. These amounts are ordinarily necessary to achieve a desired level of sweetness independent from the flavor level achieved from flavor oils. While water may be added independently with dry sweeteners, it will generally be added as part of a corn syrup or corn syrup mixture.

Suitable flavorings include both natural and artificial flavors, and mints such as peppermint, menthol, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed, essential oils (i.e. thymol, eculyptol, menthol and methyl salicylate) and the like are contemplated. The flavorings are generally utilized in amounts that will vary depending upon the individual flavor, and may, for example, range in amounts of about 0.5% to about 3% by weight of the final composition weight. The colorants useful in the present invention, include the pigments such as titanium dioxide, that may be incoφorated in amounts of up to about 1% by weight, and preferably up to about .6% by weight. Also, the colorants may include other dies suitable for food, drug and cosmetic applications, and known as F.D. & C. dyes and the like. The materials acceptable for the foregoing spectrum of use are preferably water- soluble. Illustrative examples include indigoid die, known as F.D. & C. Blue No. 2, which is the disodium salt of 5,5'indigotindisulfonic acid. Similarly, the dye known as F.D. & C. Green No. 1, comprises a triphenylmethane dye and is the monosodium salt of 4-[4-Nethyl-p- sulfobenzylamino)diphenylmethylene]-[ 1 -(N-ethyl-N-p-sulfoniumbenzyl)-

2,5-cyclohexadienimine]. A full recitation of all F.D. & C. and D. & C. and their corresponding chemical structures may be found in the Kirk- Othmer Encyclopedia of Chemical Technology, in Volume 5, at Pages 857- 884, which text is accordingly incoφorated herein by reference. Suitable oils and fats that are useable would include partially hydrogenated vegetable or animal fats, such as coconut oil, palm kernel oil, beef tallow, lard, and the like. These ingredients are generally utilized in amounts with respect to the comestible product of up to about 7.0% by weight, and preferably up to about 3.5% by weight of the final product. The weight percent of the ranitidine, or its pharmaceutically acceptable salts, based on the weight of the ranitidine adsorbate is preferably from about 1 to about 25%, and more preferably about 5 to about 20%, and most preferably about 5 to about 15%, which amount will vary depending upon the therapeutic dosage permitted and the therapeutic dosage ANC value required or permitted. Of course, the amounts will vary depending upon the therapeutic dosage permitted. The weight percent of magnesium trisilicate in the adsorbate, based on the total weight of the adsorbate, is preferably from about 0.1% to about 99%, and most preferably about 0.1% to about 75%.

The amount of ranitidine in the oral formulation is preferably in the range of from about 10 to about 600 mg, more preferably from about 10 to about 400 mg, more preferably from about 15 to about 300 mg, and in particular 25 mg, per dosage unit, expressed as the weight of free base. The unit dose may be administered, for example, one to four times daily, preferably once or twice. The exact dose will depend on the nature and severity of the condition being treated, and it may be necessary to make routine variations in the dosage depending on the age and weight of the patient. The ranitidine adsorbate is generally present with the pharmaceutically acceptable carrier in an amount of from about 1% to about 60% by weight of the final composition. The exact amount will be dependent upon the ranitidine dosage required.

The pharmaceutical compositions according to the present invention may be presented for single or multi-dose use. A single dose may for example be presented as a dry product comprising the ranitidine adsorbate (together with appropriate excipient(s)) contained in a sachet or other unit dose container. The contents may then be added to water or another suitable vehicle before use. A single dose of a non-aqueous suspension may be presented as a ready constituted suspension in a suitably designed unit pack.

The following examples are provided for illustrative puφoses only.

Examples Preparation of Ranitidine Adsorbates Example 1

Distilled deionized water was heated to a temperature of 80°C, and 200 grams of which was used to dissolve 168 grams of ranitidine hydrochloride. Magnesium trisilicate (666 grams, commercially available from Austin Chemical, Holmdel, New Jersey), having a particle size of less than about 40μm (at least 90%) and less than about 20μm (at least 80%) and having a surface area greater than about 500 m /g, was placed in a Hobart blender, and the ranitidine solution formed above was added thereto with mixing. This mixture was then blended for a sufficient period of time to achieve granulation. The resulting granulate was distributed on a paper- lined tray and dried overnight in a forced air oven at a temperature of 75°C. The dried granulate was then passed through a 20 mesh screen.

Example 2

In this example, a reduced quantity of ranitidine hydrochloride was used to prepare the ranitidine adsorbate. Accordingly, the quantity of ranitidine hydrochloride used was reduced to 118 grams, with the quantities of the remaining components being the same as in Example 1 , supra, but with the water temperature reduced to 60°C. Upon removal from the oven, the ranitidine adsorbate granulate was passed through a 20 mesh screen. Example 3

The percentage of the ranitidine component in the adsorbate was still further reduced. Here, ranitidine hydrochloride (84 grams) was placed in a beaker along with 200 grams of distilled deionized water (previously heated to a temperature of 90°C), with mixing until the ranitidine hydrochloride dissolved in the water. Magnesium trisilicate (750 grams) was placed in a Hobart blender, and the ranitidine solution formed above was added thereto with mixing. Mixing was allowed to continue for a sufficient amount of time to achieve granulation. The resulting granulate was then distributed on a paper-lined tray and overnight dried in a forced air oven at a temperature of 75°C. Upon removal from the oven, the ranitidine hydrochloride granulate was passed through a 20 mesh screen.

Example 4

Ranitidine hydrochloride (224 grams) was placed in a blender along with 650 grams of cold water, with mixing for a sufficient period of time to dissolve the ranitidine hydrochloride in the water. Magnesium trisilicate (1954 grams) was placed in a Hobart blender, and the ranitidine solution formed above was added thereto with mixing. Mixing was allowed to continue for a sufficient period of time to achieve granulation.

This period of time will of course depend on the quantities of the components chosen and the force of the mixing.

The resulting granulate was distributed on lined trays, which were then placed in a forced air oven overnight at a temperature of 50°C.

The granulate was then passed through a 20 mesh screen and stored in a plastic bag. Example 5

A ranitidine adsorbate was prepared by adding 448 grams of ranitidine hydrochloride to 600 grams of distilled deionized water, which was previously heated to a temperature of 60°C. Magnesium trisilicate (3552 grams) was placed in a Hobart blender, and the ranitidine solution formed above was added thereto with mixing. As mixing continued, an additional 650 grams of distilled deionized water (previously heated to a temperature of 60°C) was added slowly to the Hobart blender, and mixing was allowed to continue for a period of time sufficient to fiilly granulate the material.

The resulting granulate was distributed on paper-lined trays and placed in a forced air oven ovemight at 49°C. The granulate was then passed through a 20 mesh screen and placed in a plastic bag for storage.

Example 6

A ranitidine adsorbate was prepared by adding 111.6 grams of ranitidine hydrochloride to 325 grams of distilled deionized water at room temperature. Magnesium trisilicate (888.4 grams) was placed in a Hobart blender, and the ranitidine solution formed above was added thereto with mixing at 300 φm.

The resulting granulate was distributed on paper-lined trays and placed in a forced air oven ovemight at 50°C. The granulate was then passed through a 20 mesh screen and placed in a plastic bag for storage. The ranitidine adsorbate yield was 927.4 grams.

Example 7

A ranitidine adsorbate was prepared by adding 133.9 grams of ranitidine hydrochloride to 325 grams of distilled deionized water at room temperature. Magnesium trisilicate (866.1 grams) was placed in a Hobart blender, and the ranitidine solution formed above was added thereto with mixing at 300 rpm.

The resulting granulate was distributed on paper-lined trays and placed in a forced air oven ovemight at 50°C. The granulate was then passed through a 20 mesh screen and placed in a plastic bag for storage.

The ranitidine adsorbate yield was 927.9 grams.

Example 8

A ranitidine adsorbate was prepared by adding 156.2 grams of ranitidine hydrochloride to 325 grams of distilled deionized water at room temperature. Magnesium trisilicate (843.8 grams) was placed in a Hobart blender, and the ranitidine solution formed above was added thereto with mixing at 300 φm.

The ranitidine adsorbate yield was 928.9 grams.

Example 9

In an effort to improve granulation properties of the ranitidine adsorbate, polyvinylpyrrolidone was used in the method of preparing the adsorbate.

Ranitidine hydrochloride (301.5 grams) was added to a first vessel containing 650 grams of cold distilled deionized water, with stirring at room temperature until a ranitidine solution formed. In a second vessel, polyvinylpyrrolidone (136.5 grams) was added to 350 grams of cold distilled deionized water with stirring. Stirring in this second vessel continued until a thick, smooth liquid was formed. Magnesium trisilicate (2562 grams) was added to a Collette high speed mixer, followed by the slow addition of the ranitidine solution formed above, with mixing for about 5 minutes. The polyvinylpyrrolidone solution was then slowly added thereto over the course of about 5 minutes. Mixing was allowed to continue until an average amperage draw of about 3.76 was achieved. The resulting granulate was distributed on paper-lined trays and placed in a forced air oven ovemight at 49°C. The granulate was then passed through a 20 mesh screen and placed in a plastic bag for storage.

Example 10 Ranitidine hydrochloride (117.18 grams) was added to a first vessel containing 275 grams of cold distilled deionized water, with stirring at room temperature until a ranitidine solution formed. In a Hobart blender, 932.82 grams of magnesium trisilicate were added with mixing. Polyvinylpyrrolidone (50 grams) was added to a second vessel containing 150 grams of cold distilled deionized water, with stirring at room temperature for a period of about 10 minutes or until dissolved. The ranitidine solution was added slowly to the Hobart blender and blended for a period of about 5 minutes. The polyvinylpyrrolidone solution was then added slowly to the Hobart blender, and blending was allowed to continue for an additional period of five minutes.

Tablet Formulations with Ranitidine Adsorbates

Example 11

The ranitidine adsorbate of Example 2 was used to prepare tablets as follows:

Emdex (537.12 grams, com syrup solids, commercially available from Mendell, Patterson, New York) was passed through a 16 mesh screen and placed in a PK blender. The ranitidine adsorbate (420 grams), a flavoring agent (9.38 grams, grape aromalok, commercially available from Givaudan, Clifton, New Jersey), tartaric acid (18 grams), Magnasweet (2 grams, monoammonium glyczirryinate, commercially available from McAndrews & Forbes Co., Camden, New Jersey) and aspartame (7.5 grams) were then added to the blender with mixing for a period of 10 minutes. About 10% of the mixture was removed from the blender and mixed with a mold release agent (magnesium stearate (6 grams)), and then returned to the blender. Mixing was then allowed to_ continue for a period of 5 minutes.

The mixture was used at 2 grams of the final blend per tablet to prepare about 500 tablets having a hardness of about 15 scu (strong cobb unit — a unit of hardness), an outside tablet edge thickness of 0.34 inches and a middle portion thickness of about 0.28 inches.

Example 12

The ranitidine adsorbate of Example 3 was used to prepare tablets as follows:

Emdex (271.12 grams), ranitidine adsorbate (210 grams), a flavoring agent (grape aromalok (4.69 grams)), tartaric acid (7.5 grams),

Magnasweet (0.94 grams) and aspartame (3.75 grams) were passed through a 20 mesh screen and placed in a PK blender, with mixing for a period of 10 minutes. About 10% of the mixture was removed from the blender and mixed with a mold release agent (magnesium stearate (3 grams)), and then returned to the blender. Mixing was then allowed to continue for a period of 5 minutes.

The mixture was used at 2 grams per tablet to prepare about 250 tablets having a hardness of about 12 scu. Example 13

The ranitidine adsorbate of Example 5 was used to prepare tablets as follows:

Ranitidine adsorbate (1350 grams) was passed through a 20 mesh screen and placed in a PK blender. Emdex (707.01 grams), a flavoring agent (peppermint spray-dried powder (18 grams)), Cab-O-Sil M- 5 (11.4 grams, fumed silica, commercially available from Cabot Coφ., Tuscola, Illinois) and Cerelose 2001 (900 grams, commercially availab from Com Products, Summit-Argo, Illinois) were then added to the blender with mixing for a period of 10 minutes. Blending was stopped and a mold release agent (magnesium stearate (13.5 grams)) was added thereto. Blending was recommenced for an additional period of 5 minutes.

The blended mixture was used at 1.5 grams per tablet to prepare tablets having 75 mg ranitidine per tablet and having a hardness of about 5 to 8 scu.

Example 14

The ranitidine adsorbate of Example 5 was also used to prepare tablets as follows: Ranitidine adsorbate (675 grams) was passed through a 20 mesh screen and placed in a PK blender. Emdex (353.5 grams), a flavoring agent (peppermint spray- dried powder (10 grams)), Cab-O-Sil M-5 (5.7 grams), Cerelose 2001 (433.55 grams), aspartame (10.5 grams) and ACESULFAME K (5 grams) were then added to the blender with mixing for a period of 10 minutes. A mold release agent (magnesium stearate (6.75 grams)) was added thereto, and blending was allowed to continue for an additional period of 2 minutes.

The blended mixture was used at 1.5 grams per tablet to prepare 1000 compressed tablets having 75 mg ranitidine per tablet and a hardness of about 11 to 12 scu. Example 15

The ranitidine adsorbate of Example 7 was used to prepare tablets as follows:

Ranitidine adsorbate (329 grams), Emdex (393 grams), aspartame (5.5 grams) and ACESULFAME K (3 grams) were passed through a 20 mesh screen and placed in a PK blender. A flavoring agent (peppermint spray-dried powder (5 grams)), Cab-O-Sil M-5 (3 grams) and polyethylene glycol (800) (8 grams) were then added to the blender. TLe mixture was blended for a period of 7 minutes. A mold release agent _ (magnesium stearate (3.5 grams)) was added thereto, and blending was continued for an additional period of 3 minutes.

The blended mixture was used to prepare tablets at 1.5 grams per tablet.

Example 16

The ranitidine adsorbate of Example 7 was also used to prepare tablets as follows:

Ranitidine adsorbate (329 grams), Emdex (388.3 grams), aspartame (5.5 grams) and ACESULFAME K (3 grams) were passed through a 20 mesh screen and placed in a PK blender. A flavoring agent

(peppermint spray-dried powder (5 grams)), Cab-O-Sil M-5 (3 grams), polyethylene glycol (800) (12 grams) and menthol (powder) (0.7 grams) were then added to the blender. The mixture was blended for a period of 7 minutes. A mold release agent (magnesium stearate (3.5 grams)) was added thereto, and blending was continued for an additional period of 3 minutes.

The blended mixture was used to prepare tablets at 1.5 grams per tablet. Example 17

The ranitidine adsorbate of Example 6 was used to prepare tablets as follows:

Ranitidine adsorbate (395 grams), Emdex (223.3 grams), aspartame (5.5 grams), ACESULFAME K (3 grams), pregelatinized starch

1500 (25 grams), and Amerfond (77 grams, commercially available from Domino Sugar Coφoration, New York, New York) were passed through a 20 mesh screen and placed in a PK blender. Peppermint spray-dried powder (5.5 grams), Cab-O-Sil M-5 (3.7 grams), polyethylene glycol (.800) (6 grams), menthol (powder) (0.7 grams), vanilla flavor (powder) (1.8 grams) and grape flavor (powder) (0.5 grams) were then added to the blender. The mixture was blended for a period of 7 minutes. A mold release agent (magnesium stearate (3.5 grams)) was added thereto, and blending was continued for an additional period of 3 minutes. The blended mixture was used to prepare tablets at 1.5 grams per tablet.

Example 18

The ranitidine adsorbate of Example 6 was also used to prepare tablets as follows:

Ranitidine adsorbate (395 grams), mannitol (300 grams), aspartame (5.5 grams), ACESULFAME K (3 grams) and pregelatinized starch (30 grams) were passed through a 20 mesh screen and placed in a PK blender. Peppermint spray-dried powder (5.5 grams) and Cab-O-Sil M- 5 (3.5 grams) were then added to the blender. The mixture blended was for a period of 7 minutes. A mold release agent (magnesium stearate (7.5 grams)) was added thereto, and blending was continued for an additional period of 3 minutes.

The blended mixture was used to prepare tablets at 1.5 grams per tablet. Example 19

The ranitidine adsorbate of Example 10 was used to prepare tablets as follows:

Ranitidine adsorbate (263 grams), Emdex (218.4 grams), aspartame (3.7 grams) and ACESULFAME K (2 grams) were passed through a 20 mesh screen and placed in a PK blender. Peppermint spray- dried powder (3.3 grams) and Cab-O-Sil M-5 (2 grams) were then added to the blender. The mixture was blended for a period of 7 minutes. About 10% of the above-blended mixture was removed from the PK blender and blended separately with a mold release agent (magnesium stearate (2.3 grams)), and then added back to the PK blender for blending for an additional period of 3 minutes.

The blended mixture was used to prepare tablets at 1.5 grams per tablet, with the tablets having a hardness of about 15.5 scu.

Example 20

The ranitidine adsorbate of Example 10 was also used to prepare tablets as follows:

Ranitidine adsorbate (263 grams), Emdex (105 grams), mannitol (69.2 grams), a binding agent (37.8 grams, Avicel pH 102, commercially available from FMC Coφ., Philadelphia, Pennsylvania) and aspartame (14.1 grams) were passed through a 20 mesh screen and placed in a PK blender. Peppermint spray-dried powder (3.3 grams), Cab-O-Sil M-5 (2 grams) and stearic acid (4.3 grams) were then added to the blender. The mixture was blended for a period of 7 minutes. About 10%) of the above-blended mixture was removed from the PK blender and blended separately with a mold release agent (magnesium stearate (2.15 grams)), and then added back to the PK blender for blending for an additional period of 3 minutes. The blended mixture was used at 1.5 grams per tablet to prepare tablets having a hardness of about 15 scu.

Example 21 The ranitidine adsorbate of Example 10 was used to prepare additional tablets as follows:

Ranitidine adsorbate (263 grams), Emdex (107.4 grams), mannitol (granular) (80 grams), Avicel pH 102 (25 grams) and aspartame (14.1 grams) were passed through a 20 mesh screen and placed in a PK blender. Peppermint spray-dried powder (3.35 grams) and stearic acid (5 grams) were then added to the blender. The mixture was blended for a period of 7 minutes. A mold release agent (magnesium stearate (2.15 grams)) was then added to the PK blender and blending continued for an additional period of 3 minutes. The blended mixture was used to prepare tablets at 1.5 grams per tablet, with the tablets having a hardness of about 14 scu.

Example 22

The ranitidine adsorbate of Example 9 was used to prepare tablets as follows:

Ranitidine adsorbate (789 grams), Emdex (244.5 grams), mannitol (300 grams), Avicel pH 102 (75 grams) and aspartame (42 grams) were passed through a 20 mesh screen and placed in a PK blender. Peppermint spray-dried powder (12.75 grams), Cab-O-Sil M-5 (4.5 grams), malic acid (11.25 grams) and stearic acid (15 grams) were then added to the blender. The mixture was blended for a period of 7 minutes. About 10% of the above-blended mixture was removed from the PK blender and blended separately with a mold release agent (magnesium stearate (6 grams)), and then added back to the PK blender for blending for an additional period of 4 minutes. The blended mixture was used to prepare tablets at 1.5 grams per tablet, with the tablets having a hardness of about 14 scu.

Example 23 The ranitidine adsorbate of Example 10 was also used to prepare tablets as follows:

Ranitidine adsorbate (394.5 grams), Emdex (104 grams), mannitol (130 grams), Avicel pH 102 (37.5 grams), Cerelose 2001 (37.5 grams) and aspartame (20 grams) were passed through a 20 mesh screen and placed in a PK blender. Peppermint spray-dried powder (6.75 grams),

Cab-O-Sil M-5 (1.75 grams), malic acid (7.5 grams) and stearic acid (7.5 grams) were then added to the blender. The mixture was blended for a period of 7 minutes. About 10% of the above-blended mixture was removed from the PK blender and blended separately with a mold release agent (magnesium stearate (3 grams)), and then added back to the PK blender for blending for an additional period of 4 minutes.

The blended mixture was used to prepare tablets at 1.5 grams per tablet, with the tablets having a hardness of about 17 scu. This blended mixture was observed to process well, with good density, flowability and compression, as well as good release from the tablet molds.

Example 24

A series of ranitidine/magnesium trisilicate adsorbates were prepared using a spray drying process. . Water was heated to 32.2°C. The water was then agitated using a conventional stirrer, and agitation was continued throughout the process. The medicament ranitidine HCI was added and dissolved.

Magnesium trisilicate was then added in a series of additions as follows: In 10-15 seconds an amount equivalent to or less than the amount of ranitidine HCI used was added and, after stirring for 1 minute, another equivalent of magnesium trisilicate (if any) was added in the same manner. This was continued until all magnesium trisilicate was added. For processes with silicon dioxide, citric acid or acesulfame K, these compounds were now added and dissolved. The silicon dioxide, citric acid or acesulfame K were added in the same manner as the magnesium trisilicate. After addition of the compounds, the product was mixed for 20 minutes.

For processes with maltodextrin, maltodextrin was now added and dissolved. The product was then allowed to mix for 20 minutes. The product was then spray dried by a Niro Utility Dryer using an inlet temperature 160°C ± 5°C and an outlet temperature of 65°C ± 5°C. Outlet temperature was not allowed to exceed 70°C at any time during the process. Additional process parameters included: air flow of about 85 kg/hour; air pressure of about 115 psig; and spray rate of about 2600-2700 grams/hour. Slurry was kept well-agitated during drying to avoid sedimentation.

Several different runs were performed and are set forth in Tables 1 and 2 below. The amount of each ingredient employed in the runs are set forth in grams.

Table 1

Processed with A B C D E F G H Maltodextrin

Ranitidine HCI 30 20 20 20 20 — 30 30

Magnesium 270 120 140 160 180 18 270 120 Trisilicate 0

Maltodextrin 60 40 60 80 100 40 180 60 15DE

Silicon Dioxide 60

Citric Acid

Acesulfame K

Water 570 380 400 420 440 38 690 102 0 0

Processed I J K L M N O P with

Maltodextrin

Ranitidine 30 30 200 75 378.66 378.66 482 276 HCI

Magnesium 16 120 1020 382.5 2166.6 2007.2 255 3172 Trisilicate 5 8 7 4

Maltodextrin 60 60 400 150 621.34 704.98 964 552 15DE

Silicon 833.32 909.09 Dioxide

Citric Acid 60

Acesulfame 30 K

Water 52 450 3100 1425 17694. 11694. 915 1024 5 54 54 8 4 Table 2

Processed without Q R S T U Maltodextrin

Ranitidine HCI 30 — 30 30 30

Magnesium Trisilicate 270 180 180 210 240

Water 570 380 570 570 570

Example 25

Similar to Example 24, except that the amount of magnesium trisilicate was substantially less than the amount of ranitidine. All of the magnesium trisilicate was added after the ranitidine. In addition, the conditions of the spray dryer required an inlet temperature of the spray dryer set at 150°C ± 5°C and an outlet temperature of 75°C ± 5°C. The outlet temperature was not allowed to exceed 80. This example was performed as set forth in Table 3 below. The amount of each ingredient employed is set forth in grams.

Table 3

Processed with less magnesium trisilicate than ranitidine V

Ranitidine HCI 60.98

Magnesium Trisilicate (moisture value 20.5%; ANC 10.2 17.07 mEq/gm)

Maltodextrin 15DE 121.95

Water (total water adjusted up to 550 grams if solution too 400 viscous) Example 26

A ranitidine/magnesium trisilicate adsorbate was prepared using a spray drying process. The adsorbate was optionally processed with maltodextrin. The amounts of ingredients employed in the process are listed in Table 4 and 5 in grams.

Table 4

Processed with 1 2 3 4 5 6 7 Maltodextrin

Ranitidine HCI 10 10 10 10 10 10 ~

Magnesium Trisilicate 90 60 70 80 90 90 90

Maltodextrin 15DE 20 20 30 40 50 60 20

Water 190 190 200 210 220 230 190

Table 5

Processed without Maltodextrin 8 9 10 11 12

Ranitidine HCI 10 10 10 10 —

Magnesium Trisilicate 90 60 70 80 90

Water 190 190 190 190 190

Water was heated to 32.2°C. Using a conventional stirrer, agitation was begun and continued throughout the process. Ranitidine HCI was added and dissolved. Magnesium trisilicate was added in a series of additions as follows: (1) in 10-15 seconds add an amount equivalent to the amount of ranitidine HCI used; (2) stir for 1 minute then add another equivalent of magnesium trisilicate in the same manner; and (3) continue until all magnesium trisilicate is added. For processes with maltodextrin, the maltodextrin is now added and dissolved. The product was allowed to mix for 20 minutes. The mixed product was then spray dried on a Niro Utility Dryer using an inlet temperature of 160°C +/- 5 and an outlet temperature of 65°C +/-5. The outlet temperature was not allowed to exceed 70°C at any time during the process. The slurry was kept well-agitated during drying to avoid sedimentation.

Example 27

A ranitidine/magnesium trisilicate adsorbate was prepared using a spray drying process. Purified water (8 kg) was dispensed into a suitable stainless steel container and heated to 32°C +/- 2°C. Ranitidine HCI (466 gm) was added to the purified water. The solution was mixed at 400 RPM for 1 minute until the ranitidine HCI was solubilized.

Magnesium trisilicate (2602 gm) was then added to the ranitidine HGl/purified water in four equal portions while mixing until all of the magnesium trisilicate had been added. The slurry was mixed at 600 RPM for 8 minutes and at 800 RPM for an additional 4 1/2 minutes. Maltodextrin (932 gm) was then added to the slurry and mixed for 22 minutes at 800 RPM and at 1000 RPM for an additional 40 minutes. After obtaining a sample of the slurry for viscosity measurement and pH, the slurry was spray dried. The parameters of the spray drying process were as follows: feed rate of 44 ml/minute; drying gas inlet temperature of 160°C; drying gas outlet temperature of 60-70°C; and pressure of 26,000 RPM/5.2 bar. The spray rate was adjusted to achieve an exhaust temperature of 65°C +/- 5°C, the spray rate at equilibrium was 70 ml/minute.

Example 28

A ranitidine/magnesium trisilicate adsorbate was prepared using a spray drying process. Purified water (8 kg) was dispensed into a suitable stainless steel container and heated to 32°C +/- 2°C. Ranitidine HCI (265.7 gm) was added to the purified water. The solution was mixed at 400 RPM for 1 minute until the ranitidine HCI was solubilized. Magnesium trisilicate (3203.8 gm) was then added to the ranitidine

HCl/purified water in four equal portions while mixing until all of the magnesium trisilicate had been added. The slurry was mixed at 600 RPM for 16 minutes. Maltodextrin (530.8 gm) was then added to the slurry and mixed at 1200 RPM. After 1 hour and 8 minutes, an additional 1500 gms of purified water was added and mixing continued for an additional 21 minutes.

After obtaining a sample of the slurry for viscosity measurement and pH, the slurry was spray dried. The parameters of the spray drying process were as follows: feed rate of 44 ml/minute; drying gas inlet temperature of 160°C; drying gas outlet temperature of 60-70°C; and pressure of 26,000

RPM/5.2 bar. The spray rate was adjusted to achieve an exhaust temperature of 65°C +/- 5°C, the spray rate at equilibrium was 85 ml/minute.

Example 29

Ranitidine adsorbates were prepared according to Example 1 using the wet granulation method, except as provided below:

Batch Size: 2500 dose (10 mEq ANC) or 5000 dose (4.5 mEq ANC) Equipment: 25 Liter Collete/Gral High Shear Granulator

Alloy Products Coφ. Stainless Steel Pressure Pot HAGO Miniature Hollow Cone Spray Nozzle MW5 (4.1 gal/hr) CoMill Model 197-S General Procedure: I. The ranitidine HCI and binder, in separate containers, were dissolved in room temperature D.I. water. See Table 6 for quantity of water.

Table 6

Formula * No. Water for Additional Water Additional (Binder Used) Ranitidine Water #1 for Water #2

HCI Binder

None 13 750 150 0 0

Povidone 14 500 100 300 100

Maltodextrin 15 500 100 *o *o M150

None 16 800 150 0 0

Povidone K29- 17 500 100 400 100 32

Maltodextrin 18 500 100 550 100 Ml 50

Maltodextrin was added as a dry powder after the spraying of the ranitidine HCI solution had been completed and the batch worked for five minutes. After binder addition, the batch was worked until uniform (approximately 10 minutes). Efforts to add the maltodextrin as a solution resulted in extreme over wetting.

II. The dmg solution was transferred to the pressure pot. The dmg solution container was rinsed with half of the Additional Water #1. The rinse solution was added to the pressure pot and the pot pressurized to three (3) bar. III. The magnesium trisilicate was charged into the Collette/Gral bowl, the unit was closed and run for one (1) minute. (Machine settings: Chopper #1, Blade #1).

IV. The dmg solution was sprayed into the batch. No corrections for solution viscosity were made. After complete addition, the pressure pot was rinsed with the remaining Additional Water #1 and then this rinse solution was sprayed into the batch.

V. The batch was worked for at least 5 minutes after the complete addition of the liquid.

VI. The binder solution (if used) was transferred to the pressure pot. The binder solution container was rinsed with the remaining Additional Water #2. The rinse solution was added to the pressure pot and the pot pressurized to three (3) bar.

VII. The binder solution was sprayed into the batch. No corrections for solution viscosity were made. After complete addition, the spray pot was rinsed with the remaining Additional Water #2 and then this rinse solution was sprayed into the batch.

VIII. The batch was worked for at least 5 minutes after the complete addition of the liquid.

IX. The batch was wet milled through a CoMill equipped with a 2A187R037/51 screen.

X. The batch was transferred to two paper lined trays and dried in the oven for 18 hours, inlet temperature 47°C. air flow medium. XI. The batch was stored away from light in double twist tied polyethylene bags.

High Shear adsorbate Prototype Granulation: Formulations

Table 7

4.5 mEq Adsorbate 13 w/Maltodextrin binder

Material % (w/w)

Ranitidine HCI 11.5702%

Maltodextrin Ml 50 23.1405%

Magnesium trisilicate * 65.2893%

Water, DI **

Total 100.0000%

* ANC of magnesium trisilicate used 10.0 mEq/g ** Evaporates during processing

Table 8

4.5 mEq Adsorbate 14 w/Maltodextrin binder

Material % (w/w)

Ranitidine HCI 14.3010%

Maltodextrin Ml 50 5.0003%

Magnesium trisilicate * 80.6987%

Water, DI **

Total 100.0000%

ANC of magnesium trisilicate used 10.0 mEq/g

** Evaporates during processing Table 9

4.5 mEq Adsorbate 15 w/Maltodextrin binder

Material % (w/w)

Ranitidine HCI 6.5831%

Maltodextrin Ml 50 13.1661%

Magnesium trisilicate * 80.2508%

Water, DI **

Total 100.0000%

ANC of magnesium trisilicate used 10.0 mEq/g

** Evaporates during processing

Table 10

4.5 mEq Adsorbate 16 w/Maltodextrin binder

Material % (w/w)

Ranitidine HCI 7.2021%

Maltodextrin Ml 50 5.0003%

Magnesium trisilicate * 87.7975%

Water, DI **

Total 100.0000%

ANC of magnesium trisilicate used 10.0 mEq/g

** Evaporates during processing Table 11

4.5 mEq Adsorbate 17 w/Maltodextrin binder

Material % (w/w)

Ranitidine HCI 15.0538%

Magnesium trisilicate * 84.9462%

Water, DI **

Total 100.0000%

ANC of magnesium trisilicate used 10.0 mEq/g

** Evaporates during processing

Table 12

4.5 mEq Adsorbate 18 w/Maltodextrin binder

Material % (w/w)

Ranitidine HCI 7.5812%

Magnesium trisilicate * 92.4188%

Water, DI **

Total 100.0000%

ANC of magnesium trisilicate used 10.0 mEq/g

** Evaporates during processing

Example 30

A ranitidine HCI 75 mg tablet was prepared having 4.5 mEq ANC/dose. The tablet was prepared by first making a ranitidine adsorbate as follows:

Purified water was dispensed into a suitable stainless steel container and heated to 32°C +/- 2°C. Ranitidine HCI was added to the purified water. The solution was mixed at 400 RPM for 1 minute until the ranitidine HCI was solubilized.

Magnesium trisilicate was then added to the ranitidine HCl/purified water in four equal portions while mixing until all of the magnesium trisilicate had been added. The slurry was mixed at 600 RPM for 16 minutes. Each addition of magnesium trisilicate was started only after the previous addition had been completely dispersed. Maltodextrin was then added to the slurry and mixed at 1200 RPM. After 1 hour and 8 minutes, an additional 1500 gms of purified water was added and mixing continued for an additional 21 minutes.

After obtaining a sample of the slurry for viscosity measurement and pH, the slurry was spray dried. The parameters of the spray drying process were as follows: feed rate of 44 ml/minute; drying gas inlet temperature of 160°C +/- 5°C; drying gas outlet temperature of 65°C +/- 5°C; and pressure of 26,000

RPM/5.2 bar. The spray rate was adjusted to achieve an exhaust temperature of 65°C +/- 5°C, the spray rate at equilibrium was 70 ml/minute. Total processing time was 5 hours. Samples of the adsorbate were stored in twist tied double polyethylene bags in an air tight and opaque container at between 4°C and 20°C. The humidity was less than 30% RH (measured at 20°C). The preferred container was an HDPE Mauser drum.

Additional details of the adsorbate preparation are as follows: I Innggrreeddiieenntt P Peerrcceenntt WW//WW Quantity Per Batch Quantity Per Dose

Ranitidine HCI 11.65 466 gm 84 mgm

Mag. Trisilicate 65.05 2602 gm 469 mgm

Maltodextrin 23.3 932 gm 168 mgm

Water 8000 gm *Ranitidine HCI was corrected to 100% by multiplying the target weight by a correction factor. This factor was obtained by dividing the assayed weight per dose by the theoretical weight per dose (84 mgm).

**The magnesium trisilicate dose was corrected for variation in ANC by dividing the measured ANC in mEq/G into 4.24 mEq (4.24/measured ANC). The result of this calculation was the weight, in grams, of a dose of that particular lot of magnesium trisilicate. The ANC of Lot used was 10.10 mEq/gm. The rantidine tablet was then prepared by adding the ranitidine adsorbate to a V- blender. Magnesium stearate was dispersed across the surface of the granulation in the blender. After blending for about 2 minutes, the product was compressed using a suitable tablet press to certain desired specifications. The tablets were stored in twist double polyethylene bags in an air tight and opaque container at between 4°C and 20°C. The humidity was less than 30% RH (measured at 20°C). The preferred container was an HDPE Mauser drum.

Additional details of the adsorbate preparation are as follows: Ingredient Percent W/W Quantity Per Batch Quantity Per Dose

Ranitidine ADS 99.59 1442 gm 721 mgm

Mag. Stearate .41 6 gm 3 mgm

Hardness of Tablet : 10 SCU +/- 20% ANC : 4.5 mEq +/- 1.5 mEq/84 mg Ranitidine HCI

Ranitidine HCI : 84 mg +/- 10%/Tablet

Example 31 A ranitidine HCI 75 mg tablet was prepared having 10 mEq ANC/dose. The tablet was prepared by first making a ranitidine adsorbate as follows:

Purified water was dispensed into a suitable stainless steel container and heated to 32°C +/- 2°C. Ranitidine HCI was added to the purified water. The solution was mixed at 400 RPM for 1 minute until the ranitidine HCI was solubilized. Magnesium trisilicate was then added to the ranitidine HCl/purified water in four equal portions while mixing until all of the magnesium trisilicate had been added. The slurry was mixed at 600 RPM for 16 minutes. Each addition of magnesium trisilicate was started only after the previous addition had been completely dispersed. Maltodextrin was then added to the slurry and mixed at 1200 RPM. After 1 hour and 8 minutes, an additional 1500 gms of purified water was added and mixing continued for an additional 21 minutes. After obtaining a sample of the slurry for viscosity measurement and pH, the slurry was spray dried. The parameters of the spray drying process were as follows: feed rate of 44 ml/minute; drying gas inlet temperature of 160°C +/-

5°C; drying gas outlet temperature of 65°C +/- 5°C; and pressure of 26,000 RPM/5.2 bar. The spray rate was adjusted to achieve an exhaust temperature of

65°C +/- 5°C, the spray rate at equilibrium was 70 ml/minute. Total processing time was 5 hours.

Samples of the adsorbate were stored in twist tied double polyethylene bags in an air tight and opaque container at between 4°C and 20°C. The humidity was less than 30% RH (measured at 20°C). The preferred container was an HDPE

Mauser drum.

Additional details of the adsorbate preparation are as follows:

Ingredient Percent W/W Quantity Per Batch Quantity Per Dose

Ranitidine HCI 6.64 265.4 gm 84 mgm Mag. Trisilicate 80.09 3203.8 gm 1014 mgm

Maltodextrin 13.27 530 gm 168 mgm

Water 9500 gm

*Ranitidine HCI was corrected to 100% by multiplying the target weight by a correction factor. This factor was obtained by dividing the assayed weight per dose by the theoretical weight per dose (84 mgm).

**The magnesium trisilicate dose was corrected for variation in ANC by dividing the measured ANC in mEq/G into 10.24 mEq (10.24/measured ANC). The result of this calculation was the weight, in grams, of a dose of that particular lot of magnesium trisilicate. The ANC of Lot used was 10.10 mEq/gm.

The rantidine tablet was then prepared by adding the ranitidine adsorbate to a V- blender. Magnesium stearate was dispersed across the surface of the granulation in the blender. After blending for about 2 minutes, the product was compressed using a suitable tablet press to certain desired specifications. The tablets were stored in twist double polyethylene bags in an air tight and opaque container at between 4°C and 20°C. The humidity was less than 30% RH (measured at

20°C). The preferred container was an HDPE Mauser drum.

Ranitidine ADS 99.61 1899 gm 1266 mgm

Mag. Stearate .39 7.5 gm 5 mgm

Hardness of Tablet : 10 SCU +/- 20%

ANC : 10 mEq +/- 1.5 mEq/84 mg Ranitidine HCI

Ranitidine HCI : 84 mg +/- 10%/Tablet

Example 32 A chewable ranitidine HCI 75 mg tablet was prepared having 4.5 mEq

ANC/dose. The tablet was prepared by first making a ranitidine adsorbate as follows:

Magnesium trisilicate was then added to the ranitidine HCl/purified water in four equal portions while mixing until all of the magnesium trisilicate had been added. The slurry was mixed at 600 RPM for 16 minutes. Each addition of magnesium trisilicate was started only after the previous addition had been completely dispersed.

Maltodextrin was then added to the slurry and mixed at 1200 RPM. After 1 hour and 8 minutes, an additional 1500 gms of purified water was added and mixing continued for an additional 21 minutes. After obtaining a sample of the slurry for viscosity measurement and pH, the slurry was spray dried. The parameters of the spray drying process were as follows: feed rate of 44 ml/minute; drying gas inlet temperature of 160°C +/- 5°C; drying gas outlet temperature of 65°C +/- 5°C; and pressure of 26,000 RPM/5.2 bar. The spray rate was adjusted to achieve an exhaust temperature of 65°C +/- 5°C, the spray rate at equilibrium was 70 ml/minute. Total processing time was 5 hours. Samples of the adsorbate were stored in twist tied double polyethylene bags in an air tight and opaque container at between 4°C and 20°C. The humidity was less than 30% RH (measured at 20°C). The preferred container was an HDPE Mauser drum.

Ranitidine HCI 11.65 466 gm 84 mgm

Mag. Trisilicate 65.05 2602 gm 469 mgm Maltodextrin 23.3 932 gm 168 mgm

Water 8000 gm

*Ranitidine HCI was corrected to 100% by multiplying the target weight by a correction factor. This factor was obtained by dividing the assayed weight per dose by the theoretical weight per dose (84 mgm). **The magnesium trisilicate dose was corrected for variation in ANC by dividing the measured ANC in mEq/G into 4.24 mEq (4.24/measured ANC). The result of this calculation was the weight, in grams, of a dose of that particular lot of magnesium trisilicate. The ANC of Lot used was 10.10 mEq/gm.

The chewable rantidine tablet was then prepared by first passing magnesium stearate and approximately 60 grams of microcrystalline cellulose through a 30 mesh screen. The two ingredients were then combined. Next, sodium chloride, monosodium citrate, mannitol, aspartame, silicon dioxide, and any remaining microcrystalline cellulose and di-pac tabletting sugar were also screened through a 30 mesh screen. The screened ingredients were then combined in a V-blender with the ranitidine adsorbate. After blending for about

10 minutes, the previously screened magnesium stearate and microcrystalline cellulose were also added to the blender. After blending for about 2 minutes, the blended material was either discharged into double polyethylene lined HDPE drums or compressed into tablets. Ingredient Percent W/W Quantity Per Batch Quantity Per Dose

Ranitidine ADS 48.067 1802.5 gm 721 mgm

Di-Pac 65.05 35.467 1330 gm 532 mgm

Microcrys. Cel 5.33 200 gm 80 mgm

Mannitol 6.667 250 gm 100 mgm

Sod. Chloride 1.333 50 gm 20 mgm

Aspartame 1.333 50 gm 20 mgm

Monosod. Citrate 1.333 50 gm 20 mgm

Silicon Dioxide 2.5 2.5 gm 1 mgm

Mag. Stearate 15 15 gm 6 mgm

Hardness of Tablet : 10 SCU +/ - 20%

ANC : 4.5 mEq +/- 1.5 mEq/84 mg Ranitidine HCI

Ranitidine HCI 84 mg +/- 10%/Tablet

Example 33

Powder X-ray diffraction studies were performed to determine the physical state of ranitidine HCI in a ranitidine adsorbate sample. The ranitidine adsorbate was prepared according to Example 1 using the wet granulation method, except as provided below:

To a slurry of magnesium trisilicate (45 grams) in water (150 grams) ranitidine HCI (5 grams) was added at room temperature and stirred for 2 hours. The slurry was filtered under vacuum on a sintered glass funnel. The filtered cake was dried at 37°C for 16 hours.

Powder X-ray diffractometry: The sample was filled in an aluminum holder and exposed to CuKα radiation (45 kV x 30mA) in a wide-angle X-ray diffractometer increments of 0.05°2Θ. The angular range was 5 to 40°2Θ, and counts were accumulated for 1 second at each step.

Results of adsorbate sample: The powder pattern (Figure 1) reveals only a single peak at approximately 38.5°2Θ. This peak is due to the aluminum sample holder. Peaks due to crystalline ranitidine HCI were not seen in the powder pattern.

Results of heated adsorbate sample: It was of interest to perform powder X-ray diffractometry of a heated adsorbate sample. Therefore, the adsorbate was heated up to 300°C, quench cooled and reheated to 175°C. Three samples were collected, and because of the small sample size (about 5 mg), it was necessary to use a specially fabricated low background holder. The X-ray powder pattern (Figure 2) did not reveal the presence of any crystalline powder.

Example 34

Powder X-ray diffraction studies were performed to determine the physical state of ranitidine HCI and ranitidine HCI in a ranitidine adsorbate sample. The ranitidine adsorbate was prepared with and without maltodextrin according to the following procedure using the spray-dried method as described for Lots A and Q in Example 24.

Powder X-ray diffractometry. The sample was filled in an aluminum holder and exposed to CuKα radiation (45 kV x 30mA) in a wide-angle X-ray diffractometer (Model D500 Siemens). The instrument was operated in the step scan mode, in increments of 0.05°2Θ. The angular range was 5 to 40°2Θ, and counts were accumulated for 1 second at each step.

Results of ranitidine HCI: The powder X-ray diffraction pattern (Figure 3) reveals that ranitidine HCI is a crystalline compound. Results of ranitidine adsorbate (Lot Q): The powder X-ray diffraction pattern (Figure 4) suggests that the compound is amoφhous to X-rays. Results of ranitidine adsorbate + maltodextrin (Lot A): The powder X-ray diffraction pattern (Figure 5) suggests that the compound is amoφhous to X-rays. The powder pattern was very similar to that of the ranitidine adsorbate prepared without maltodextrin. Example 35

Powder X-ray diffraction studies were performed to determine the physical state of ranitidine HCI in several different ranitidine adsorbate samples. The ranitidine adsorbates were prepared according to Examples 29 (13-18) using the wet granulation method.

Results of ranitidine adsorbate (Example 29-13): The powder X-ray diffraction pattern (Figure 6) suggests that the compound is amoφhous to X-rays.

Results of ranitidine adsorbate (Example 29-14): The powder X-ray diffraction pattern (Figure 7) suggests that the compound is amoφhous to X-rays. Results of ranitidine adsorbate (Example 29-15): The powder X-ray diffraction pattern (Figure 8) suggests that the compound is amoφhous to X-rays.

Results of ranitidine adsorbate (Example 29-16): The powder X-ray diffraction pattern (Figure 9) suggests that the compound is amoφhous to X-rays. Results of ranitidine adsorbate (Example 29-17): The powder X-ray diffraction pattern (Figure 10) suggests that the compound is amoφhous to X-rays.

Results of ranitidine adsorbate (Example 29-18): The powder X-ray diffraction pattern (Figure 11) suggests that the compound is amoφhous to X-rays.

Example 36 Powder X-ray diffraction studies were performed to determine the physical state of ranitidine HCI in a ranitidine adsorbate sample. The ranitidine adsorbate was prepared according to Example 25 using the spray-dried method. Powder X-ray diffractometry. The sample was filled in an aluminum holder and exposed to CuKα radiation (45 kV x 30mA) in a wide-angle X-ray diffractometer (Model D500 Siemens). The instrument was operated in the step scan mode, in increments of 0.05°2Θ. The angular range was 5 to 40°2Θ, and counts were accumulated for 1 second at each step. Results of ranitidine adsorbate (Example 25): The powder X-ray diffraction pattern (Figure 12) suggests that the compound is amoφhous to X-rays.

Example 37

Powder X-ray diffraction studies were performed to determine the physical state of ranitidine HCI in two different ranitidine adsorbate samples. The ranitidine adsorbate was prepared according to Example 27 and 28 using the spray-dried method.

Results of ranitidine adsorbate (Example 27): The powder X-ray diffraction pattern (Figure 13) suggests that the compound is amoφhous to X-rays.

Results of ranitidine adsorbate (Example 28): The powder X-ray diffraction pattern (Figure 14) suggests that the compound is amoφhous to X-rays.

Example 38 A study was performed to determine the stability of ranitidine HCI in five different ranitidine adsorbate samples. The ranitidine adsorbate were prepared according to Example 24, Lots O & P, and 30-32 using the spray-dried method. The stability of the adsorbates was tested under accelerated conditions over a twelve week period at 30°C/80 relative humidity or 40°C/75 relative humidity. The results of the stability studies are shown in Table 13. Table 13 Ranitidine HCI adsorbate (Example 24, Lot O) 30C/60RH

TIMEPOINT RANITIDINE RANITIDINE RELATED

(weeks) CONTENT (%) IMPURITIES (%) BASE (INITIAL) Total

Initial 10.86 (100%) 0.11

1 10.90 (100.4%) 0.20

2 10.73 (98.8%) 0.16

4 10.31 (94.9%) 0.15

8 10.59 (97.5%) 0.33

12 10.48 (96.5%) 0.62

Ranitidine HCI adsorbate (Example 24, Lot P) 30C/60RH

TIMEPOINT RANITIDINE RANITIDINE RELATED

(weeks) CONTENT (%) IMPURITIES (%) BASE (INITIAL) Total

Initial 6.01 (100%) 0.29 1 6.07 (101%) 0.50 2 5.95 (99.0%) 0.64 4 5.62 (93.5%) 0.86 8 5.64 (93.8%) 1.73 12 5.58 (92.8%) 1.9

Ranitidine HCI adsorbate (Example 24, Lot P (dried)) 30C/60RH

TIMEPOINT RANITIDINE RANITIDINE RELATED

(weeks) CONTENT (%) IMPURITIES (%) BASE (INITIAL) Total

Initial 6.07 (100%) 0.30

1 6.15 (101.3%) 0.41

2 6.02 (99.2%) 0.54

4 5.87 (96.7%) 0.66

8 5.90 (97.2%) 1.01

12 5.87 (96.7%) 1.19 Ranitidine adsorbate tablet (Example 30) 30C/80RH

TIMEPOINT RANITIDINE CONTENT % RANITIDINE (weeks) BASE (INITIAL) RELEASED

IMPURITIES(%)

Total

Initial 10.44 (100.0%) 0.09

1 10.43 (99.9%) 0.06

4 10.29 (98.6%) 0.07

8

12

Ranitidine adsorbate tablet (Example 31) 30C/80RH

TIMEPOINT RANITIDINE CONTENT % RANITIDINE

(weeks) BASE (INITIAL) RELEASED IMPURITIES

(%) Total

Initial 5.87 (100.0%) 0.21

1 5.71 (100.7%) 0.37

4 5.52 (97.4%) 0.73

8

12

Ranitidine OTC chewable (Example 32) 30C/80RH

TIMEPOINT RANITIDINE CONTENT % RANITIDINE RELEASED (weeks) BASE (INITIAL) IMPURITIES (%)

Total

Initial 5.00 (100.0%) 0.08

1 4.83 (96.6%) 0.12

4 4.85 (97.5%) 0.14

8

12

Example 31 A dissolution test was performed on five ranitidine tablets prepared in accordance with Example 32. In addition, a dissolution profile was conducted on three additional tablets.

Initially, five tablets were tested for dissolution in 900 mL of 0.1N HCI (at 37°C) at a paddle speed of 50 RPM for 45 minutes. The samples were then assayed using HPLC techniques with UV detection at a wavelength of 322nm. The results from the dissolution test at 45 minutes are as follows in Table 14 for six tablets tested:

Table 14

SAMPLE TABLET SAMPLE Mg RANITIDINE Mg/gram % OF NUMBER WEIGHT VOLUME FOUND RANITIDINE THEORY

1 1.5585 gm 900 ML 68.6 44.0 88.4%

2 1.5655 gm 900 ML 68.4 43.7 87.7%

3 1.5475 gm 900 ML 68.6 44.3 89.0%

4 1.546 gm 900 ML 69.4 44.9 90.1%

5 1.5385 gm 900 ML 71.2 46.3 92.9%

6 1.5568 gm 900 ML 69.7 44.8 89.9%

Analysis performed HPLC Theory: 49.8 mg/gram

The data showed an average recovery of 89.7% of ranitidine base from the tablets with a 2.03% RSD. The dissolution profile of three additional tablets was performed at 5, 10, 15, 30 and 45 minutes. After the 45th minute the paddle speed was increased from 50 RPM to 200 RPM and a final sample was taken at the 120th minute of dissolution. This final time point was taken to determine the greatest possible recovery when the tablet is completely dissolved. The results are reported in Table 15 as the percent ranitidine dissolved of the 75.8 mg theoretical dose (as determined by the assay value of 101.1%).

Table 15

Wavelength: 322 nm Theory: 49.8 mg/gra

TRIAL TIME POINT TABLET SAMPLE Mg RANITIDINE Mg/gram % OF NUMBER (minutes) WEIGHT VOLUME FOUND RANITIDINE THEORY

5 1.5588 gm 900 ML 27.8 17.8 35.8% 10 1.5588 gm 880 ML 46.0 29.5 59.3% 15 1.5588 gm 860 ML 56.7 36.2 73.0% 30 1.5588 gm 840 ML 66.2 42.5 85.3% 45 1.5588 gm 820 ML 67.0 43.0 86.3% 120¹ 1.5588 gm 800 ML 73.4 47.1 94.6%

2 5 1.4952 gm 900 ML 21.0 14.0 28.2% 2 10 1.4952 gm 880 ML 38.8 25.9 52.1% 2 15 1.4952 gm 860 ML 48.9 32.7 65.7% 2 30 1.4952 gm 840 ML 63.1 42.2 84.7% 2 45 1.4952 gm 820 ML 66.8 44.7 89.7% 2 120¹ 1.4952 gm 800 ML 76.2 51.0 102.3%

3 5 1.4803 gm 900 ML 24.2 16.3 32.8% 3 10 1.4803 gm 880 ML 42.9 29.0 58.2% 3 15 1.4803 gm 860 ML 52.6 35.5 71.4% 3 30 1.4803 gm 840 ML 63.8 43.1 86.5% 3 45 1.4803 gm 820 ML 65.9 44.5 89.4% 3 120¹ 1.4803 gm 800 ML 74.5 50.3 101.1%

After the 45th minute the paddle speed was increased to 200 RPM.

This time point is taken to determine the maximum dissolution possible.

Analysis Performed by HPLC Dissolution Media: 0.1 N HCI

Example 39

Compatibility studies were conducted on ranitidine HCl/citric acid as well as ranitidine HCl/malic acid by using Perkin Elmer series 7 Differential Scanning Calorimeter. Each binary mixture was at 1/1 weight ratio. The results are presented in Figures 15-16. Same studies were repeated for ranitidine HCI adsorbate and citric acid or malic acid mixtures, the adsorbate being prepared according to the spray-drying process of Example 28. The data is shown in Figures 17-18. Figures 15-16 indicate ranitidine HCI is not compatible with either citric acid or malic acid. Exothermic interactions for ranitidine HCl/citric acid and ranitidine

HCl/malic acid occurred at 135° and 130°C, respectively. However, corresponding exothermic peaks do not appear in Figures 17-18.

While the present invention has been described with respect to what is presently considered to be the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. To the contrary, the invention is intended to cover various modifications and equivalent formulations included within the spirit and scope of the appended claims. The scope of the following claims is to be accorded the broadest interpretation so as to encompass all such modifications and equivalent formulations and functions.

Claims

WHAT IS CLAIMED IS:

1. A ranitidine adsorbate which consists essentially of magnesium trisilicate containing adsorbed therein ranitidine or a physiologically acceptable salt thereof, the ranitidine is amorphous and stable.

2. The ranitidine adsorbate according to Claim 1 wherein said salt is ranitidine hydrochloride.

3. The ranitidine adsorbate according to Claim 1 wherein said magnesium n trisilicate has a surface area of at least 400 m /g.

4. The ranitidine adsorbate according to Claim 1 wherein said ranitidine or physiologically acceptable salt thereof is present in the adsorbate in an amount of from about 1% to about 15% by weight based on the total weight of the adsorbate.

5. The ranitidine adsorbate according to Claim 1 wherein the magnesium trisilicate is present in the adsorbate in an amount of from about 85% to about 99% by weight based on the total weight of the adsorbate.

6. The ranitidine adsorbate according to Claim 1 wherein the adsorbate further consists of a coating agent.

7. The ranitidine adsorbate according to Claim 6 wherein the coating agent is maltodextrin.

8. The ranitidine adsorbate according to Claim 1 wherein the adsorbate further consists of a second dmg in combination with the ranitidine.

9. The ranitidine adsorbate according to Claim 1 wherein a range from about

60% to about 75% of ranitidine is released within 15 minutes and 80% to about 90% of ranitidine is released within 45 minutes from the adsorbate.

10. A ranitidine adsorbate which consists essentially of magnesium trisilicate having a surface area of at least 400 m /g contained therein ranitidine or a physiologically acceptable salt thereof, the ranitidine is amorphous and stable.

11. The ranitidine adsorbate according to Claim 10 wherein said salt is ranitidine hydrochloride.

12. The ranitidine adsorbate according to Claim 10 wherein said ranitidine or physiologically acceptable salt thereof is present in the adsorbate in an amount of from about 1% to about 15% by weight based on the total weight of the adsorbate.

13. The ranitidine adsorbate according to Claim 10 wherein the magnesium trisilicate is present in the adsorbate in an amount of from about 85% to about 99% by weight based on the total weight of the adsorbate.

14. The ranitidine adsorbate according to Claim 10 wherein the adsorbate further consists of a coating agent.

15. The ranitidine adsorbate according to Claim 14 wherein the coating agent is maltodextrin.

16. The ranitidine adsorbate according to Claim 10 wherein the adsorbate further consists of a second dmg in combination with the ranitidine.

17. The ranitidine adsorbate according to Claim 10 wherein a range from about 60% to about 75% of ranitidine is released within 15 minutes and 80% to about 90% of ranitidine is released within 45 minutes from the adsorbate.

18. A pharmaceutical composition comprising the ranitidine adsorbate according to Claim 1 in the form of chewable, suckable, or swallowable tablets.

19. A pharmaceutical composition comprising the ranitidine adsorbate according to Claim 1 in the form of granules.

20. A pharmaceutical composition comprising the ranitidine adsorbate according to Claim 1 in the form of an aqueous dispersion.

21. A pharmaceutical composition comprising the ranitidine adsorbate according to Claim 1 in the form of a non-aqueous suspension.

22. A pharmaceutical composition comprising the ranitidine adsorbate according to Claim 1 in the form of capsules, powders, or lozenges.

23. A method for making a ranitidine adsorbate, comprising:

(a) dissolving ranitidine or its physiologically acceptable salt in a solvent to form a solution;

(b) mixing the solution with magnesium trisilicate as the sole adsorbate to form a homogeneous dispersion; and

(c) recovering ranitidine adsorbate.