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WO2025219929A1 - Préparation d'un hydrate de raloxifène pour traiter le cancer et l'ostéoporose - Google Patents

Préparation d'un hydrate de raloxifène pour traiter le cancer et l'ostéoporose

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Publication number
WO2025219929A1
WO2025219929A1 PCT/IB2025/054042 IB2025054042W WO2025219929A1 WO 2025219929 A1 WO2025219929 A1 WO 2025219929A1 IB 2025054042 W IB2025054042 W IB 2025054042W WO 2025219929 A1 WO2025219929 A1 WO 2025219929A1
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Prior art keywords
rlx
hydrate
hci
arg
pharmaceutical composition
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English (en)
Inventor
Emmanuel KIYONGA
Poka MADAN
Witika BWALYA
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Sefako Makgatho Health Sciences University
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Sefako Makgatho Health Sciences University
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Publication of WO2025219929A1 publication Critical patent/WO2025219929A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane

Definitions

  • the present invention relates to a method of producing a hydrate of Raloxifene (RLX) with increased solubility and to a hydrate of RLX produced according to the method.
  • the invention also relates to pharmaceutical compositions comprising a hydrate of RLX prepared according to the method.
  • the invention further relates to a hydrate of RLX or pharmaceutical compositions comprising the hydrate of RLX for use in methods of preventing and/or treating osteoporosis and/or cancer.
  • the hydrate of RLX produced by combining a coformer mixture of RLX-HCI and Arginine .
  • Raloxifene is a nonsteroidal selective oestrogen receptor modulator (SERM) that has been approved by the FDA for the treatment of osteoporosis and to lower the risk of invasive breast cancer in postmenopausal women.
  • SERM selective oestrogen receptor modulator
  • Raloxifene was specifically developed in order to maintain the beneficial estrogenic activity on bone and lipids and to exert anti- oestrogenic activity on endometrial and breast tissue.
  • Raloxifene works by inducing conformational changes in the oestrogen receptor, which in turn, enables the expression of certain oestrogen- regulated genes in different tissues. For instance, the agonist properties of raloxifene on bone tissues were recently attributed to the activation of the human transforming growth factor-b3 gene, which is generally regarded to be essential in bone remodelling.
  • RLX is a class II Biopharmaceutical Classification System (BCS) active pharmaceutical ingredient (API), which has previously been shown to exhibit poor solubility and high permeability.
  • BCS Biopharmaceutical Classification System
  • Raloxifene HCI has a molecular weight of 510.05 g-mol" 1 . It is off-white to pale yellow non-volatile solid. Its solubility in water is 627.4 ⁇ 132.0 pg mL -1 and it is classified as very slightly soluble in water.
  • Raloxifene HCI is absorbed rapidly after oral administration and has an absolute bioavailability of about 2%. The drug has a half-life of about 28 h and is eliminated primarily in the faeces after hepatic glucuronidation.
  • Raloxifene hydrochloride salts are usually used orally, therefore the solubility in gastric juice, where the main constituent is diluted hydrochloric acid, is particularly important. Specifically, due to the low pH and the presence of chloride ions, the solubility of any salt used decreases close to the solubility level of raloxifene hydrochloride.
  • the present invention relates to a Raloxifene hydrate having improved solubility and bioavailability, and to uses thereof.
  • the present invention relates to a hydrate of Raloxifene (RLX), with increased solubility and bioavailability and also relates to a method of producing the hydrate of RLX. Also described herein are pharmaceutical compositions comprising a hydrate of RLX. The invention further relates to methods of preventing and/or treating osteoporosis and/or cancer using the hydrate of RLX, as well as to compositions for use in methods of preventing and/or treating osteoporosis and/or cancer.
  • RLX Raloxifene
  • a method for producing a hydrate of Raloxifene comprising: a) combining RLX, or a salt thereof, with an amino acid to form a co-former mixture; b) dissolving the co-former mixture in a solvent to form a solution; and c) evaporating the solvent from the solution to form a hydrate of RLX.
  • Figure 3 PXRD diffractograms acquired for RLX-HCI, Arg, and the synthesized hydrate of RLX-HCl-Arg in molar ratios of 2:1 , 1 :1 , and 1 :2 through solvent evaporation with corresponding physical mixtures.
  • the present invention pertains to novel hydrates of Raloxifene and their methods of synthesis, wherein protection is extended to encompass a broad range of synthesis conditions, reactants, and methodologies.
  • the Raloxifene hydrate can be synthesized using varying molar ratios of RLX-HCI to amino acids, including but not limited to 2:1 , 1 :1 , and 1 :2.
  • the present invention encompasses any ratio of RLX-HCI to amino acid that results in the formation of the Raloxifene hydrate, including ratios that may deviate from those explicitly disclosed herein. It is a particular aim of the present invention to provide for the preparation of Raloxifene hydrate with improved solubility and bioavailability. The problem of poor solubility and consequent low bioavailability is solved by the introduction of hydrate into the raloxifene hydrochloride molecule.
  • the solvent evaporation technique was used to develop a hydrate of the Raloxifene with amino acids as co-formers.
  • the inventors of the present invention show herein that RLX-HCI and amino acid arginine (Arg) in ethanol as the solvent exhibited the best combination for crystal formation after characterisation and led to improved solubility and bioavailability of Raloxifene HCI.
  • RLX-HCI amino acid arginine
  • Arg amino acid arginine
  • the inventors used RLX-HCI as the starting material, combining it with an amino acid, preferably Arg. After the synthesis process, the final product did not include HCI and Arginine, although the inventors determined that HCI and Arginine played a significant role in forming the hydrate of Raloxifene.
  • raloxifene as used herein means the selective oestrogen receptor modulator molecule known as raloxifene having the IUPAC name: [6-hydroxy-2-(4-hydroxyphenyl)- benzothiophen-3-yl]-[4-[2-(1 -piperidyl)ethoxy]phenyl]-methanone, and includes any other name therefor, such as Keoxifene, Pharoxifene, LY-139481 , LY-156758, CCRIS-7129. In some embodiments, the term may encompass known salts and derivatives thereof.
  • RLX-HCI hydrochloride salt form of Raloxifene
  • RLX-HCI hydrochloride salt form of Raloxifene
  • RLX-HCI neutral (free base) form of Raloxifene
  • Alternative salts of RLX may also be employed in the method of producing the hydrate of RLX, including but not limited to salts of RLX obtained by reacting RLX with hydrobromic acid, acetic acid, tartaric acid, or methanesulfonic acid. The scope of this invention therefore extends to the use of any pharmaceutically acceptable form of RLX in the RLX hydrate synthesis method.
  • hydrate formulation There are different methodologies for hydrate formulation, including (i) solvent evaporation without heat; (ii) solvent evaporation with heat; (iii) solvent evaporation with heat and cooling; and (iv) recrystallization.
  • a formulated sample of RLX-HCI with Arginine using the solvent evaporation technique may not form the crystals but a large particle-size powder. This powder can be further re-crystalized by placing it in methanol or ethanol and leaving for at least 3 to 7 days without stirring or agitation and without adding any heat, to allow for the growth of crystals.
  • Another method that can be used to grow crystals is to place samples of RLX and Arg in a solvent (ethanol or methanol) without agitation or heat and leave the samples for at least 3 to 7 days, allowing the precipitate to grow clear crystals.
  • another method comprises placing a sample of RLX-HCl-Arginine into a test tube with 10ml ethanol, heating it at 78 °C while stirring at 200rpm until the ethanol boils, allowing it to cool-down for one minute then extracting the top clear solution, transferring it into another test tube and then placing the test tube in a beaker with ice or placing it in a fridge. Visible crystals will form if the sample is refrigerated for at least 3 to 7 days after the solvent has evaporated.
  • solvents such as ethanol and methanol.
  • the invention is not limited to these solvents alone and extends to any pharmaceutically acceptable solvent that facilitates hydrate formation, including but not limited to isopropanol, dimethyl sulfoxide (DMSO), ethyl acetate, water, or any other related solvent.
  • DMSO dimethyl sulfoxide
  • the present invention also encompasses any isomeric or polymorphic forms of the hydrate that may arise during synthesis. This includes but is not limited to stereoisomers, tautomers, and conformational isomers of the hydrate structure. Any hydrate exhibiting substantially similar physicochemical properties and therapeutic efficacy is considered within the scope of this invention. Additionally, any crystalline or amorphous forms resulting from the disclosed methods are included within the scope of the invention.
  • subject includes mammals, preferably human or animal subjects, but most preferably the subjects are human subjects.
  • subject and patient are used interchangeably herein.
  • the invention also includes pharmaceutical compositions comprising an effective amount of a fatty acid raloxifene derivative and a pharmaceutically acceptable carrier.
  • the invention includes a fatty acid raloxifene derivative provided as a pharmaceutically acceptable prodrug, hydrate, salt, such as a pharmaceutically acceptable salt, enantiomers, stereoisomers, or mixtures thereof.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium,
  • preventing when used in relation to a medical disease or condition, is well understood in the art, and includes administration of a composition which reduces the frequency of or delays the onset of symptoms of a condition in a subject relative to a subject which does not receive the composition.
  • the terms “improve”, “ameliorate”, and “heal” are used interchangeably and refer to when one or more symptoms of a particular disease, disorder or condition is reduced in magnitude (e.g., intensity, severity, etc.) and/or frequency.
  • therapeutic treatment is well known to those of skill in the art and includes administration to a subject of one or more of the hydrates or pharmaceutical compositions of the invention. If the composition is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilise the existing unwanted condition or side effects thereof).
  • disorder means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition comprising the compound to a subject or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.
  • prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a fatty acid raloxifene derivative.
  • Suitable formulations or compositions to administer the pharmaceutical compositions of the present invention to subjects fall within the scope of the invention.
  • Any appropriate route of administration may be employed, such as, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, intracistemal, intraperitoneal, intranasal, or oral administration.
  • an “effective amount” of a hydrate or pharmaceutical composition according to the invention includes a therapeutically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as treatment of osteoporosis and/or breast cancer.
  • the outcome of the treatment may for example be the prevention of osteoporosis, cancer metastasis, preventing recurrence of the cancer, a decrease in cancer markers, a decrease in tumour size, inhibition of target metabolic pathways, delay in development of a pathology associated with cancer, or any other method of determining a therapeutic benefit.
  • a therapeutically effective amount of a composition may vary according to factors such as the disease state, age, sex, and weight of the individual, the ability of the composition to elicit a desired response in the individual, previous therapeutic treatments, the nature and severity of the cancer or osteoporosis to be treated, the route of administration, and the form of the composition. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects.
  • an effective amount of the hydrates, or compositions of the invention will be administered to a subject.
  • an effective amount of the hydrate of the present invention can be provided, either alone or in combination with other compounds, or they may be linked with suitable carriers and/or other molecules.
  • Toxicity and therapeutic efficacy of compositions of the invention may be determined by standard pharmaceutical procedures in cell culture or using experimental animals, such as by determining the LD 5 o and the ED 5 o. Data obtained from the cell cultures and/or animal studies may be used to formulate a dosage range for use in a subject.
  • the dosage of any composition of the invention lies preferably within a range of circulating concentrations that include the ED 5 o but which has little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilised.
  • the therapeutically effective dose may be estimated initially from cell culture assays.
  • Dosage values may vary and be adjusted over time according to the individual need and the judgment of the person administering or supervising the administration of the hydrates or pharmaceutical compositions or compounds of the invention. It may be advantageous to formulate the hydrates or compositions in dosage unit forms for ease of administration and uniformity of dosage.
  • RLX-HCI Pure RLX was extracted from RLX-HCI for possible use in the method of obtaining a hydrate of RLX, however it was decided to conduct the further experiments using RLX-HCI.
  • Amounts varied with increase in weight by x1 (51.004 mg: 17.02 mg), X2 (102.008 mg: 34.04), X5 (255.02 mg: 85.1 mg), X8 (408.032 mg: 136.16 mg), X10 (510.04 mg: 170.2 mg) and X20 (1 .02008 g: 340.4 mg).
  • the mixture was not heated or stirred; however, the sample was left for 3 days until a precipitate formed at the bottom of the beaker. A crystal looking cake formed after 3 days. The sample was filtered using filter paper and the remaining solvent was left to evaporate.
  • a sample of the powder was placed into a test tube and 5mls of methanol was added. No stirring occurred and the sample was placed in an enclosed cupboard for 4 days to allow for the methanol to completely evaporate.
  • Raloxifene HCI 51 Omg
  • Arginine (170mg) in equi-molar ratios of 1 :1
  • 10ml of ethanol was added into the test tube which was then placed on a magnetic stirrer. Stirring was set at 200rpm for 30 minutes and temperature was set at 78°C until the ethanol reached its boiling point.
  • the test tube was allowed to cool down for at least 1 minute and was then placed into a beaker with ice. The mixture was then left for an hour until the ice melted.
  • the beaker with the test tube was then placed into the fridge for 3-7 days.
  • the resultant crystals were characterized on the FTIR, HSM, and DSC.
  • the study utilized a fast-screening process to assess the co-former feasibility in developing crystalline systems. These included citric acid, maleic acid, tartaric acid, malonic acid, gallic acid, L-tyrosine, phenylalanine, L-arginine, L-tryptophan, proline, glycine, and stearic acid which are all GRAS (generally regarded as safe) elements.
  • the preliminary screening procedure was employed to identify the suitable co-formers in the preparation of RLX-HCI hydrate.
  • 4 different co-formers which included phenylalanine, tyrosine, tryptophan, and arginine were evaluated using the Hansen solubility parameter (HSR) and the pKa based models.
  • HSR Hansen solubility parameter
  • the Hansen solubility parameter (HSP) was used on RLX-HCI to predict the co-crystal formation between RLX-HCI and the co-formers.
  • the HSP values of the co-formers were compared with those of RLX-HCI to determine whether the two materials were likely to be compatible and form crystalline systems as part of the theoretical prediction of potential cocrystal formation.
  • the HSP can provide a first approximation of the likelihood of co-crystal formation.
  • Co-formers with a smaller Delta value are typically more likely to form hydrate with the drug substance, as their similar solubility characteristics may lead to enhanced molecular interactions and stability in the solid state.
  • the HSP for RLX-HCI, HCI, and various co-formers are provided in Table 1.
  • the HSP values are divided into three components which include dispersion (5D), polar (bP), and hydrogen bonding (bH), along with the total HSP (bT) and a delta value (ST of RLX-HCI - ST of co-former), which is the difference in solubility parameter between the drug and the coformer.
  • the delta values represent the radius of the Hansen sphere or the distance in the Hansen space between the drug and each co-former. A smaller delta value indicates a closer match in the Hansen space and suggests better compatibility between the drug and the coformer for co-crystal formation.
  • L-Arginine and phenylalanine have the smallest delta values when paired with Raloxifene, with L-arginine having the Abt value of 3.2 and phenylalanine having 2.9.
  • Citric acid 17.6 1 1.4 26.0 33.4 -7.5
  • the pKa based model was used as a pharmacokinetic model to predict the absorption, distribution, metabolism, and elimination of RLX-HCL Hydrochloride (HCI) based on its acid dissociation constant (pKa) values in relation to the pKa values of the co-formers.
  • HCI RLX-HCL Hydrochloride
  • 2 pKa values, including the strongest acidic as well as the strongest basic were used for each co-former in relation to the API. The difference between the pKa of the strongest acidic and the strongest basic was then determined for the API as well as the other co-formers.
  • the pKa (acid dissociation constant) based model was used for the prediction of the acid dissociation constants of the co-formers.
  • a ApKa between 0-3 indicates that either a co-crystal or salt may form.
  • a ApKa greater than 3 indicates the formation of salts as is the case with citric acid, tartaric acid and gallic acid with ApKa of 3.72, 4.12 and 3.52 respectively.
  • Table 2 pKa based model results for RLX-HCI with different co-formers.
  • the present study explored the possibility of preparing RLX-HCl-hydrate using amino acids Rhe, Tyr, Trp and Arg as co-formers.
  • the hydrate were further investigated with the aid of DSC, HSM, FTIR and XRD.
  • the binary physical mixtures (PMs) of RLX-HCl-Phe, RLX-HCI- Tyr, RLX-HCl-Trp and RLX-HCl-Arg prepared by gently grinding the accurately weighed (Radwag analytical balance, Radom, Tru) quantities of RLX-HCI (API) and Phe, Tyr, Trp, and Arg (co-formers) at different drug to co-former molar weight ratios of 2:1 , 1 :1 and 1 :2 (w/w).
  • the components were then placed in a test tube and mixed using a mortar and pestle. Approximately 5-10 ml of analytical grade ethanol or methanol was added to dissolve the RLX- HCL-co-former mixture, and the components were mixed with a Z83 vortex mixer (FisherbrandTM, Milan, Italy) for at least 30 seconds.
  • the test tube was placed under fume cupboards at room temperature to allow the solvent to evaporate. The resultant mixtures were further left to completely dry in a desiccator prior to characterisation.
  • a re-crystallization technique was used for optimization of the RLX-HCl-Arg hydrate.
  • FTIR Fourier Transform Infrared Spectroscopy
  • Arginine in contrast, demonstrates distinct peaks at 3302 cm -1 and 3357 cm' 1 , attributable to the guanidine and primary amine groups, respectively.
  • RLX-Arg (2:1 ) crystals a new absorption peak at 3530 cm' 1 is observed, alongside an alteration at 3350 cm- 1 .
  • the peak at 3530 cm -1 may denote the formation of a new hydrogen-bonded species, suggesting an interaction between the N-H groups of RLX-HCI and the guanidine or amine groups of Arg.
  • the 3350 cm' 1 alteration could be attributed to a shift in the hydrogen bonding pattern of Arg’s guanidine group.
  • the RLX-Arg (1 :1 ) crystals displays similar spectral features, with the 3530 cm' 1 peak indicating a strong interaction between the components, potentially due to the equimolar presence facilitating optimal hydrogen bond formation.
  • the peak at 3350 cm' 1 in this ratio could reflect the balanced interaction between the guanidine group of Arg and the functional groups of RLX-HCI.
  • the RLX-Arg (1 :2) crystals, where Arg is in excess still shows the new peak at 3530 cm' 1 , but the intensity and shape of this peak may differ, reflecting the altered stoichiometry and the possible saturation of hydrogen bonding sites on RLX-HCI.
  • the broadening of the peaks in the 1140-1228 cm' 1 region across all mixtures is indicative of an interaction affecting the C-N bond, potentially due to an overlap of the vibrations from both RLX-HCI and Arg. This broadening becomes more pronounced with increasing Arg content.
  • the elongation of the spectra in the 3100-3300 cm -1 region for all mixtures denotes a deviation from the absorption patterns of both RLX-HCI and Arg, which is indicative of a complex interaction between the N-H and O-H stretching vibrations, potentially altering the hydrogen bonding network.
  • the FTIR spectra of the RLX-Arg crystals exhibit significant deviations from the spectra of the individual components, RLX-HCI and Arg.
  • the RLX-Arg (1 :1 ) PM spectrum indicates that the mixing of RLX-HCI and Arg in equal proportions does not result in significant changes in the O-H and N-H regions.
  • the preservation of the original peaks from both components implies that the physical mixture does not exhibit new intermolecular interactions that are detectable by FTIR spectroscopy.
  • the RLX-HCI and Arg physical mixtures in the molar ratios, largely retain their individual spectral characteristics, indicating minimal interaction, particularly in the form of hydrogen bonding, within the limitations of FTIR detection.
  • the FTIR spectra of RLX-Arg physical mixtures at different ratios (2:1 , 1 :1 , 1 :2) suggest that the mixing of RLX-HCI and Arg does not lead to significant molecular interactions that alter the vibrational frequencies. This is evidenced by the preservation of characteristic peaks of both components in the mixtures, with the spectrum of the 1 :2 mixture closely resembling that of Arg due to its predominance in the mixture.
  • DSC Differential scanning calorimetry
  • thermograms provided in Figure 2 offer insight into the thermal behaviour of RLX-HCI, Arg, and their hydrate at different molar ratios (2;1 , 1 :1 and 1 :2).
  • RLX-HCI the thermogram exhibits a distinct and sharp endothermic peak at 268.8 °C, which is indicative of the melting point of the substance. This confirms the purity and identity of the RLX-HCI sample.
  • the sharpness of the peak suggests a pure crystalline phase with a well-defined melting transition.
  • the thermogram shows a complex thermal behaviour.
  • the initial small endothermic peak at 100.1 °C can be attributed to a dehydration effect, likely due to the loss of water molecules from the arginine sample.
  • the reported melting points in the literature are 220.7°C and 241 .7 °C and the differences could be due to variations in the sample purity or experimental conditions.
  • the crystals at a 2:1 molar ratio showed a shift in the thermal events compared to the individual components.
  • the peak observed at a slightly lower temperature, 98 °C can be ascribed to dehydration.
  • the subsequent melting peaks at 127 °C and 184 °C do not align with the pure substances' melting points. This suggests the formation of a solid solution or a complex between RLX-HCI and Arg, altering the thermal behavior.
  • these melting peaks could indicate a eutectic formation, where the mixture melts at a lower temperature than either of the pure components, or it could be indicative of a solid dispersion where one drug is molecularly dispersed within the crystal lattice of the other, leading to depression of the melting point.
  • the singular endothermic peak at 129.3 °C suggests a significant alteration in phase behavior, likely due to the formation of a new compound or a eutectic mixture or formation of a hydrate.
  • Eutectic mixtures occur when two components exhibit complete miscibility in the liquid phase but limited solubility in the solid phase, leading to a combined melting point that is lower than either component alone.
  • the presence of only one peak implies that the RLX-HCI and Arg have interacted to form a new phase with a unique thermal signature, distinct from either pure compound.
  • the 1 :2 crystals presents a dehydration peak similar to the 2:1 crystals but follows with endothermic peaks at 126 °C and 181 °C. Again, these temperatures do not match the melting points of the pure compounds, suggesting the formation of a new phase, possibly a eutectic or a compound with a depressed melting point due to the solid solution formation. In all mixtures, the absence of endothermic peaks corresponding to the pure components' melting points suggests that the RLX-HCI and Arg are not merely physically mixed but chemically or physically interacting. These interactions could be hydrogen bonding, van der Waals forces, or ionic interactions, potentially leading to hydrates or eutectic mixtures especially in the RLX- Arg (1 :1 ) ratio.
  • the PXRD diffractograms of the pure and prepared samples were recorded using a D2 phaser XE-T Edition (Brucker, Massachusetts, United States of America). The operations used a Cu Ka radiation with a voltage of 40 kV, and 40 Ma current. The divergent slit of the machine was set at 0.2 mm and monochromator scanning was performed at a scan speed of 20 per minute with step size of 0.025°.
  • the unique set of peaks indicates that Arg has a crystalline structure that is distinct from RLX-HCI.
  • the absence of shared peaks implies no polymorphic similarities between the two compounds in their pristine forms.
  • the crystal derived from RLX-Arg in a 2:1 molar ratio displays peaks at 20.3°, 21.9°, 23.8°, and 25.1 °. The disappearance of most peaks from the individual compounds indicates a significant interaction that alters the original crystalline structures, possibly leading to the formation of a new phase.
  • the visible peaks being more reflective of RLX-HCI suggest that at this ratio, the RLX-HCI crystal lattice dominates, possibly encapsulating Arg within its structure.
  • the appearance of new, distinct, and sharp peaks, especially at high intensities (10.9° and 28.2°) indicates the formation of a new crystalline phase entirely.
  • the presence of these peaks indicates a less complete interaction compared to the 1 :1 ratio, with the Arg structure seemingly more prominent in the mixture. This suggests that the Arg crystalline network has a stronger influence on the resulting structure, with RLX-HCI possibly integrating into the Arg lattice.
  • the greater number of peaks and their alignment with those of pure RLX-HCI and Arg suggest that the crystalline structures of both components are preserved in the mixture. This indicates that there is no significant interaction at the molecular level that would lead to the formation of a new crystalline phase. Instead, the mixture represents an additive combination of the two crystalline patterns.
  • the thermal melting behavior of the samples was investigated using a Linkam u-p03 hot stage microscope (Olympus, Tokyo, Japan), employing objective lenses with 4X and 10X magnification capabilities.
  • the samples were subjected to a controlled temperature program with a ramp of 10 °C/min, spanning a broad thermal spectrum from an initial temperature of 25 °C to an upper limit of 300 °C. This methodological approach facilitates the precise determination of melting and other thermal events pertinent to the samples under investigation.
  • Hot-stage microscopy was utilized to scrutinize the thermal dynamics and phase transitions of RLX-HCI, Arginine, and their crystals across varying ratios.
  • the experiments were conducted at a heating rate of 10 °C/min, enabling detailed observation of the samples' behavior during thermal excursions.
  • RLX-HCI exhibited a first melting event at 260 °C, with complete melting occurring at 269.2 °C, consistent with the DSC findings.
  • Arginine displayed its initial melting at 249.3 °C, with complete melting observed at 254.3 °C, aligning well with the DSC observations.
  • the HSM micrographs illustrated in Figure 4 showed the onset of melting at the designated temperature, followed by the disappearance of solid structures, indicative of the transition to a liquid phase. This behavior is consistent with the principles of thermal analysis, where the observed melting temperatures correspond to the energy required to overcome the intermolecular forces holding the crystalline lattice together.
  • the observed melting temperatures and thermal behavior during the HSM analysis were in agreement with the results obtained from differential scanning calorimetry (DSC), providing corroborative evidence of the samples' thermal characteristics.
  • DSC differential scanning calorimetry
  • the HSM analysis facilitated a comprehensive understanding of the thermal properties and phase transitions of RLX-HCI, Arginine, and their crystals across different ratios.
  • SEM Scanning Electron Microscopy
  • EDX Energy-dispersive X-ray Spectroscopy
  • the shape and surface morphology of the formulated samples were viewed using the SEM SUPRA 55 VP, Carl Zeiss, Oberkochen (Baden-Wurttemberg, Germany) at a 2 kV accelerating voltage.
  • the samples will be lightly sprinkled, mounted on aluminum stubs using double-sided adhesive carbon tape, and then sputter coated with approximately 15 nm gold using a Quorum T150 ES coater (Eastshire, United Kingdom) before imaging.
  • the appearance of the samples was photographed using a camera.
  • These prepared samples were further analysed under varying degrees of magnification to ascertain their elemental composition and distribution. The examination was conducted using an Oxford Instruments X-Max 50mm 2 EDX detector (Abingdon, Oxfordshire, United Kingdom).
  • SEM images shown in Figure 5 indicate RLX-HCI at 150 times magnification.
  • the image shows elongated, rod-like structures typical of crystalline forms.
  • Arg is shown at 60 times magnification showing relatively large, irregularly shaped particles with a rough surface, indicating a different crystal habit.
  • RLX-Arg PM (1 :1 ) is a physical mixture of RLX- HCI and Arg in a 1 :1 ratio, observed at 106 times magnification.
  • the image shows a more heterogeneous mixture of particles, where both the elongated structures of RLX-HCI and the irregular shapes of Arg are visible. This suggests that in the physical mixture, the two substances retain their individual characteristics without forming a new compound.
  • RLX-Arg (1 :1 ) is a sample of RLX-HCI and Arg in a 1 :1 ratio, imaged at 100 times magnification. Without additional context, it's unclear whether this represents a crystal, a solid solution, or another form of compound such as a hydrate or eutectic. However, the image shows a more homogeneous morphology compared to the physical mixture, suggesting some form of interaction between RLX and Arg, suggesting a crystallization or a more intimate mixing at the molecular level.
  • Intensity data was determined on a Bruker D8 Venture Microfocus with Photon III CCD area detector diffractometer with graphite-monochromated MoK1 (0.71073 A) radiation at 173 K using an Oxford Cryostream 600 cooler. Data reduction was carried out using the program SAINT+, version 6.02 and empirical absorption corrections were made using SADABS. Space group assignments was made using XPREP. The structure was solved in the WinGX Suite of programs, using intrinsic phasing through SHELXT and refined using full-matrix least- squares/difference Fourier techniques on F using SHELXL-2019/3.
  • the SCXRD analysis revealed that the RLX-Arg (1 :1 ) compound had an empirical formula C28H29NO5S as shown in Table 3.
  • the SCXRD was crucial in gaining significant insights into its molecular and crystal structure of this sample.
  • the compound, having a molecular weight of 491.58, was studied at a low temperature of 173 K (-100.15 °C). This low temperature is crucial in minimizing thermal vibrations within the crystal lattice, allowing for more precise and less distorted diffraction patterns. Such clarity is essential for accurate structural determination.
  • the crystal system was monoclinic, and the space group C 2/c indicates a specific kind of symmetry and molecular packing within the crystal. This information is critical for understanding the intermolecular interactions and the overall stability of the crystal.
  • a large unit cell volume of 5493.5 A 3 in combination with the crystal system and space group, suggests a complex arrangement of molecules within the crystal. With a calculated density of 1.189 Mg/m 3 , the material's interactions with light and X-rays can be inferred, affecting its absorption properties.
  • the absorption coefficient of 0.154 mm -1 also provides information on how X-rays are absorbed by the crystal, which is crucial for adjusting the parameters of the diffraction experiment.
  • the crystal size although relatively small (0.398 x 0.206 x 0.165 mm 3 ), was sufficient for the collection of a large number of reflections (103245), indicating a good quality crystal.
  • This high number of reflections along with a completeness of 99.9% up to a theta of 25.242°, demonstrates the high quality of the data collected, ensuring reliability in the resulting structural model.
  • Figure 6 represents the molecular structure of RLX-Arg (1 :1 ) as determined by the SCXRD.
  • ORTEP diagram which provides a visual representation of the atomic positions and their thermal vibration.
  • the atoms are represented by ellipsoids, which show the thermal motion at a particular probability level.
  • Hydrogen atoms are usually depicted as small spheres or circles attached to their respective carbons. The bonds between atoms are depicted as solid lines, while dashed lines indicate hydrogen bonding or other non-covalent interactions.
  • the structure suggests a complex organic molecule with multiple rings, likely aromatic given the delocalized pi-electron systems implied by the ring structures.
  • the presence of oxygen and nitrogen atoms suggests functional groups that may include ketones, ethers, or amines, which are common in pharmaceutical compounds or natural organic products.
  • arginine in the Single Crystal X-ray Diffraction (SCXRD) structure of the compound synthesized from RLX-HCI and Arg may be due to several factors.
  • One possibility is that during the solvent evaporation process, arginine did not co-crystallize with RLX-HCI. This could occur if the conditions favored the crystallization of RLX-HCI alone, possibly due to its higher concentration or a more favorable crystal packing arrangement.
  • Arginine, being more soluble might have remained in the solvent phase. Solubility differences are a common reason for the lack of co-crystallization in multi-component systems. Another reason could be related to the stoichiometry of the reaction used to synthesize the compound.
  • the resulting crystal may not have included arginine in its lattice. It's also possible that arginine was present initially but decomposed or reacted during the crystallization process. Conditions such as pH, temperature, or the presence of other reactive species could lead to the degradation or transformation of arginine into different species that did not incorporate into the crystal lattice. Furthermore, the interaction between RLX-HCI and Arg might be non-stoichiometric or too weak to survive the crystallization process.
  • the intended non-covalent interactions e.g., hydrogen bonding, ionic interactions
  • the intended non-covalent interactions may not be strong enough to withstand the conditions during solvent evaporation, leading to the formation of a crystal lattice that excludes one of the components.
  • the intended non-covalent interactions e.g., hydrogen bonding, ionic interactions
  • the intended non-covalent interactions may not be strong enough to withstand the conditions during solvent evaporation, leading to the formation of a crystal lattice that excludes one of the components.
  • a Shimadzu (Kyoto, Japan) HPLC system consisting of a pump (LC-20AD), an autosampler (SIL-20AHT), UV detector (SPD-M20A), and Lab solutions software were utilised. Prior to injection of the drug solution, the column was equilibrated for at least 25 min with the mobile phase flowing through the system.
  • the API, RLX-HCI was analysed at 287 nm using a Shimadzu Shim-pack GIST column, 150 x 4.6 mm; 5pm particle size (Tokyo, Japan) at ambient temperature.
  • a mobile phase consisting of a buffer and acetonitrile in the ratio 64:36 (v/v), at a flow rate of 1.0 mL/min and an injection volume of 50 pL injection volume was used.
  • the buffer consisted of 50 mM potassium di-hydrogen ortho phosphate monohydrate, with pH adjusted to 3.0 using ortho-phosphoric acid. They were filtered through 0.45p membrane filter before use, degassed and were pumped from the solvent reservoir. Drug concentration was calculated by using the calibration curve in the range of 2.5 - 15 pg/mL, with a correlation coefficient (r2) of 0.9991 .
  • the RLX-HCI concentration was measured in triplicate and the mean ⁇ SD were reported in Table 4.
  • Table 5 Samples run on the HPLC in triplicate with the mean area under the curve calculated as well as the concentrations.
  • the concentration is relatively low for both RLX-HCI and RLX- Arg (1 :1 ), indicating that the drug and its hydrate may not be fully dissolved or ionized at this acidic pH.
  • the acidic environment may not be favourable for the solubility of RLX-HCI or newly formulated its hydrate, possibly due to protonation of the RLX-HCI, which reduces their solubility.
  • the pH is increased to 4.5, a substantial increase in the concentration of RLX- HCI to 1.8 pg/ml is observed, indicating improved solubility at this pH level.
  • the concentration of the RLX-Arg (1 :1 ) hydrate does not increase to the same extent, which could be due to the different solubility profiles of the hydrate compared to RLX-HCI, possibly because of interactions between the RLX-HCI and Arg in the hydrate or the removal of Arg as observed in the SCXRD data.
  • the concentration of RLX-Arg (1 :1) only increases to 0.41 pg/ml, suggesting that the hydrate may have different solubility characteristics possibly due to the formation of a less soluble complex when the solvent was incorporated into the crystal lattice and the loss of the HCI salt as observed in the SCXRD data.
  • the concentration of both RLX-HCI and RLX-Arg (1 :1 ) decreases, with RLX-HCI showing a more significant reduction. This trend may be due to the ionization state at a higher pH where the drug is less ionized, reducing its solubility. It could also be indicative of the formation of less soluble aggregates at this pH. It is at this pH however where the solubility of the hydrate was greater than that of the drug.
  • the hydrate formulation could potentially improve RLX-HCI solubility in the intestinal environment.
  • Improved solubility often facilitates better dissolution rates and higher concentrations of the drug in the gastrointestinal tract, which are key factors in enhancing oral absorption.
  • the hydrate form of RLX-HCI exhibits decreased lipophilicity, this alteration appears to be strategically advantageous for increasing the drug's bioavailability in the intestinal environment, thereby potentially improving its overall absorption profile.
  • RLX-HCI were determined in 900 mL of pH 6.8 (phosphate buffer) at 37 ⁇ 0.5°C with a stirrer rotation speed of 75 rpm using the USP dissolution test apparatus type II (paddle type) ERWEKA DT 128 light series (Langen, Germany).
  • the RLX- HCI-co-former systems were taken equivalent to 100 mg of RLX-HCI with an aliquot of 5 mL of sample withdrawn at 5, 10, 15, 25, 30, 60,120, and 720 min, filtered through 0.45-micron filter, suitably diluted and transferred into HPLC vials. Samples were analysed at wavelength of 287 nm in triplicate.
  • DE dissolution efficiency
  • Table 6 shows the cumulative drug release over time
  • Figure 8 is a representation of in vitro dissolution profiles of RLX-HCI and RLX-Arg (1 :1 ) potential crystal.
  • the graph in Figure 8 shows the cumulative drug release percentage of RLX-HCI, and its hydrate with Arg, RLX-Arg (1 :1 ) over time, measured in minutes.
  • Initial observations reveal that both RLX-HCI and RLX-Arg (1 :1 ) demonstrate a rapid release within the first 50 minutes, achieving approximately 80% dissolution. This initial burst is typical for drugs with high solubility or those that have been processed to enhance dissolution, such as through co-crystallization.
  • the slight improvement in dissolution rate for RLX-Arg (1 :1 ) could be attributed to the improved wettability, reduced particle size, altered crystal habit, or increased porosity of the crystals compared to pure RLX-HCI.
  • the increased dissolution rate of the RLX-Arg (1 :1 ) hydrate could lead to faster onset of action, which can be crucial for the therapeutic application of the drug.
  • the partition coefficient or Log P is a critical parameter in pharmacokinetics, describing how a compound distributes itself between a hydrophobic (organic) phase and a hydrophilic (aqueous) phase.
  • a hydrophobic (organic) phase describing how a compound distributes itself between a hydrophobic (organic) phase and a hydrophilic (aqueous) phase.
  • RLX-Arg (1 :1 ) sample was dissolved in a water-octanol (10ml) solvent system. Magnetic stirrers were used to stir the mixture for a period of 36 hours. The solution was then centrifuged in a Hettich Rotofix 32A centrifuge (Andreas Hettich GmbH & Co., Tuttingen, Germany) for 45 minutes to allow them to separate the two phases of solution, octanol, and water.
  • a positive Log P value such as 1 .1 1
  • a positive Log P value indicates that the compound is more soluble in the organic phase (octanol) than in the aqueous phase. This is also evident in the concentration of the hydrate in octanol, shown in Table 7, being greater than that in water 18.31 pg/ml and 1.43 pg/ml, respectively.
  • This hydrophobic character is essential for understanding how the compound behaves in biological systems, particularly in terms of membrane permeability.
  • Compounds with a Log P in the range of 1 -3 are generally well absorbed, as they possess enough lipophilicity to pass through lipid bilayers in biological membranes but are not so lipophilic that they get trapped in fatty tissues.
  • the Log P value of the hydrate suggests it should have good oral bioavailability as a result of good drug absorption, a key consideration in drug design.
  • An intermediate Log P value, such as 1.11 indicates a favorable balance, potentially leading to better absorption and bioavailability.
  • Raloxifene hydrochloride (RLX-HCI), molecular formula C28H27NO4S-HCI, molar mass 510.04 RLX-HCI is a highly lipophilic drug with a Log P value of 5.69. A higher Log P (like 5.69 for RLX-HCI) suggests that the substance is more lipophilic and less hydrophilic. This can imply greater solubility in lipids and less in water.
  • the lower Log P as is the case with 1.1 1 for RLX-Arg (1 :1 ) hydrate suggests it is less lipophilic and more hydrophilic, implying increased water solubility and decreased lipid solubility as compared to RLX-HCL
  • the RLX-HCI with a higher Log P will generally be better absorbed through the lipid-rich cell membranes and may have a broader distribution in the body's lipid compartments.
  • the hydrate with a lower Log P might be less efficiently absorbed but could have a more restricted distribution, potentially reducing its presence in lipid-rich tissues. Therefore, the hydrate, with its significantly lower Log P, indicates better water solubility, potentially leading to different pharmacokinetics and pharmacodynamics, and could be advantageous in certain therapeutic contexts.
  • Lipinski's Rule of Five is a set of guidelines used in drug discovery to predict the drug likeness of compounds, particularly their oral bioavailability. These rules are based on the observation that most orally active drugs have certain common physicochemical properties. It is important to note that Lipinski's Rule of 5 serves as a guideline rather than a strict rule. However, compounds that meet these criteria are more likely to have good oral bioavailability and be suitable for further development. These rules act as a quick and simple filter to prioritize compounds for further testing and optimization in drug discovery. If a compound violates one or more of these rules, it may not be disqualified as a potential drug candidate, but additional studies and modifications are usually required to address the issues related to bioavailability and permeability.
  • the Lipinski’s rule of five suggests that poor absorption or permeation is more likely if the molecular weight (MW) is over 500 Dalton, the number of hydrogen bond donors (the sum of O-H and N-H) is more than 5, the number of hydrogen bond acceptors (the sum of N’s and O’s) is more than 10 and the logarithm of the partition coefficient between n-octanol and water (log 10P) is greater than 5.
  • the molecular weight of the RLX-Arg (1 :1 ) hydrate is 491 .58 Da as per the ORTEP diagram from the SCXRD. This is slightly below the 500 Da threshold, indicating that the compound may have acceptable molecular size for oral bioavailability.
  • the compound has 3 hydrogen bond donors. This meets the rule's threshold, suggesting that the number of hydrogen bond donors is within the acceptable range for oral drugs.
  • RLX-Arg (1 :1 ) hydrate is well within the acceptable limit of 10.

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Abstract

L'invention concerne un procédé de production d'un hydrate de raloxifène (RLX) présentant une solubilité accrue et un hydrate de RLX produit selon le procédé. L'invention concerne également des compositions pharmaceutiques comprenant un hydrate de RLX préparé selon le procédé. L'invention concerne en outre un hydrate de RLX ou des compositions pharmaceutiques comprenant l'hydrate de RLX destiné à être utilisé dans des méthodes de prévention et/ou de traitement de l'ostéoporose et/ou du cancer. En particulier, l'hydrate de RLX est préparé par combinaison d'un mélange co-formateur de RLX, ou d'un sel de celui-ci, et d'arginine.
PCT/IB2025/054042 2024-04-18 2025-04-17 Préparation d'un hydrate de raloxifène pour traiter le cancer et l'ostéoporose Pending WO2025219929A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011047878A2 (fr) * 2009-10-23 2011-04-28 Hexal Aktiengesellschaft Procédé de préparation de dérivés de benzo[b]thiophène

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011047878A2 (fr) * 2009-10-23 2011-04-28 Hexal Aktiengesellschaft Procédé de préparation de dérivés de benzo[b]thiophène

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GREENHALGH, D. J.WILLIAMS, A. C.TIMMINS, P.YORK, P.: "Solubility parameters as predictors of miscibility in solid dispersions", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 88, 1999, pages 1182 - 1190, XP000853397, DOI: 10.1021/js9900856
MOHAMED, S.TOCHER, D.A.PRICE, S.L.: "omputationa re iction of saltand cocrystaf structures-Does a proton position matter?", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 418, no. 2, 2011, pages 187 - 198
NAGY, S., S. PALA. SZÉCHENYI: "Reliability of the Hansen solubility parameters as co-crystal formation prediction tool", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 558, 2019, pages 319 - 327, XP085598488, DOI: 10.1016/j.ijpharm.2019.01.007
THAYYIL, A. R.JUTURU, T.NAYAK, S.KAMATH, S.: "Pharmaceutical co-crystallization: Regulatory aspects, design, characterization, and applications", ADVANCED PHARMACEUTICAL BULLETIN, vol. 10, 2020, pages 203

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