GULBRA-009 DOUBLE ACTIVATED BASIC ALUMINUM CHLORIDE COMPOSITIONS OF HIGH PERFORMANCE COMPRISING OF BUFFERING AGENTS AND METHODS OF MAKING SAME CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of the filing date of U.S. Provisional Application No. 63/542,170, filed October 3, 2023, the disclosure of which is incorporated herein by reference. BACKGROUND [0002] Basic aluminum chlorides (BAC) are known effective antiperspirants. BACs used as antiperspirants include aluminum chlorohydrate (ACH) having an Al/Cl molar ratio ranging from 1.91 to 2.1, aluminum sesquichlorohydrate (ASCH) having an Al/Cl molar ratio ranging from 1.26 to 1.90, or aluminum dichlorohydrate (ADCH) having an Al/Cl molar ratio ranging from 0.91 to 1.25. [0003] To improve antiperspirant efficacy of BACs, one conventional method involves introducing zirconium compounds and amino acids into BACs for efficacious aluminum-zirconium antiperspirants. However, there are drawbacks. First, aluminum-zirconium antiperspirant actives are expensive due to the high cost of zirconium. Second, aluminum-zirconium antiperspirant actives cannot be used in aerosol formulations due to the potential hazard of zirconium compounds. [0004] Another conventional method involves manufacturing BAC solutions with a low Al/Cl molar ratio. These solutions have increased efficacy due to the higher quantity of depolymerized species, such as aluminum monomers and dimers, as demonstrated by HPLC peak 5. However, there are drawbacks. First, irritancy is challenging for formulation, specifically with skin compatibility and fragrance stability. Second, the spray dryer, which is used to turn a solution into a powder, is quickly corroded because the high acid content causes heavy acid loss. It is challenging to activate BAC at low Al/Cl mole ratio, such as an Al/Cl mole ratio lower than 1.5, to achieve high HPLC peak 4. It is also challenging to activate the HPLC peak 4 while keeping HPLC peak 5 high. Therefore, there is no commercially activated BAC having an Al/Cl molar ratio from about 0.9:1 to about 1.5:1. [0005] Conventionally, solutions with a high Al/Cl mole ratio, such as an Al/Cl mole ratio above 1.5, is created when ACH and ASCH solutions are diluted and thermally treated. However, these solutions are not stable and revert to HPLC peak 3 aluminum species during cooling and aging. Therefore, to preserve the high HPLC peak 4, the solutions are quickly dried to powders. Those powders have high HPLC peak 4 of at least 30% and low peak 5 of less than 10%. Additionally, solutions with a low Al/Cl mole ratio, such as an Al/Cl mole ratio below 1.5, the process of dilution, heat treatment, and drying does not result in high peak 4 aluminum salts. Upon drying, the high HPLC peak 4 will revert to HPLC peak 3 and peak 5, and heavy loss of acid occurs. Thus, activated BAC salts at low Al/Cl mole ratios usually have high HPLC peak 5 and low peak 4. [0006] It is highly desirable to provide activated BAC products having both high HPLC peak 4 and peak 5 with superior efficacy and reduced skin irritancy. It is also highly desirable to provide an
GULBRA-009 effective method of manufacturing the activated BAC products having both high HPLC peak 4 and peak 5 with superior efficacy and reduced skin irritancy. BRIEF DESCRIPTION OF THE DRAWING [0007] Figure is
27Al NMR of Example 4-I of an AADCH-Glycine solution in Table 12. BRIEF SUMMARY [0008] The present disclosure is directed to an antiperspirant active composition of high efficacy including a double-activated aluminum salt and a buffering agent. The buffering agent may be an amino acid, betaine, urea, or a mixture thereof. The composition has an aluminum to chloride (Al:Cl) molar ratio ranging from 0.9:1 to 1.8:1 and a size exclusion chromatography HPLC peak 4 of at least 20% and peak 5 of at least 10%. The resulting solution has improved stability so that the solutions can be dried into a powdered form before the solution gels. [0009] One aspect of the disclosure is directed to an antiperspirant active powder including a double-activated aluminum salt and a buffering agent of an amino acid, betaine, urea, or a mixture thereof. An HPLC peak 4 may be at least 20% and an HPLC peak 5 may be at least 10%. An aluminum to chlorine (Al/Cl) molar ratio may range from 0.9:1 to 1.8:1. [0010] In some examples, the HPLC peak 4 may be below 65%, and the HPLC peak 5 may be below 55%. [0011] In some examples, the powder does not include calcium or zirconium. [0012] In some examples, the aluminum salt may be represented by Chemical Formula 1: Al2(OH)6-aXa. X may be selected from the group consisting of Cl and NO3, and a may range from 1.0 to 6.6. [0013] In some examples, the double-activated aluminum salt may be activated aluminum dichlorohydrate (AADCH) or activated aluminum sesquichlorohydrate (AASCH). [0014] In some examples, the amino acid may be glycine. In some examples, a glycine concentration may range from 1% to 25% by weight. [0015] Another aspect of the disclosure is directed to a topical composition including an effective amount of the antiperspirant active powder as described above and a dermatologically acceptable carrier. In some examples, the topical composition may be in the form of a liquid for a roll-on or porous applicator, a lotion, a cream, a soft-solid stick, a solid stick, or an aerosol. In some examples, the topical composition may further include cyclomethicone, behenyl alcohol, polypropylene glycol (PPG) 15 stearyl ether, isopropyl myristate, polyethylene, alkyl c12-15 benzoate, hydrogenated castor oil, talc, or colloidal silica. [0016] Another aspect of the disclosure is directed to a method of preparing a double-activated basic aluminum chloride (BAC) solution. The method may include preparing a first solution by mixing a diluted aluminum salt solution and a first acid. The aluminum salt may be at least one of ACH or ASCH. The method may also include thermally treating the first solution to at a temperature ranging from 80°C to 100°C for a range of 8 to 16 hours. The method may also include cooling the first solution to a temperature
GULBRA-009 of 50°C or below. The method may also include preparing a second solution by mixing a second acid and a buffer of an amino acid, betaine, urea, or a mixture thereof. The method may also include co-mixing the first solution and the second solution. [0017] In some examples, the first solution may have a mole per kg aluminum concentration ranging from 0.74 to 3.75. In some examples, the second solution may have a mole per kg glycine strength ranging from 1.4 to 1.85. [0018] In some examples, at least one of the first acid or second acid may be HCl, H2SO4, HNO3, AlCl3, Al2(SO4)3 or Al(NO3)3. [0019] In some examples, the drying step may include spray drying the solution to a solid. [0020] Another aspect of the disclosure is directed to a method of preparing a double-activated basic aluminum chloride (BAC) solution. The method may include mixing an aluminum salt solution, an acid, and a buffer of an amino acid, betaine, urea, or a mixture thereof to form a first solution. The aluminum salt may be at least one of ACH or ASCH. The method may also include thermally treating the first solution at a temperature ranging from 80°C to 100°C for a range of 6 to 12 hours. [0021] In some examples, at least one of the first acid or second acid may be HCl, H2SO4, HNO3, AlCl3, Al2(SO4)3 or Al(NO3)3. [0022] In some examples, the drying step may include spray drying the solution to a solid. DETAILED DESCRIPTION [0023] A double-activated basic aluminum chlorides (BAC) solution having both high HPLC peak 4 and peak 5 may be created through both heat activation and acid activation of BAC in a solution with a buffering agent. The presence of the buffering agent in the double-activated BAC solution may provide more depolymerized and activated aluminum species, leading to higher performance. The acid activation, in addition to the heat activation, may preserve high HPLC peak 4 aluminum species and may generate more depolymerized aluminum species aluminum monomers and dimers represented by HPLC peak 5, such that double-activated aluminum species are produced. The buffering agent may be a water- soluble amino acid. The amino acid includes, but not limited to, glycine, alanine, valine, arginine, or a mixture thereof. Additionally, the buffering agents may be betaine, urea, or a mixture thereof of these example buffering agents, amino acids, or any other buffering agents. In some aspects, the buffering agent may be glycine. [0024] The BAC-Buffer solution may not contain calcium or zirconium. [0025] In some aspects, the double-activated BAC-Buffer solution may have an HPLC peak 4, for example, of at least 20%, at least 30%, or at least 35% and below 65%. [0026] In some aspects, the double-activated BAC-Buffer solution may have an HPLC peak 5, for example, of at least 10%, at least 15%, or at least 20% and below 55%.
GULBRA-009 [0027] The method may include diluting BAC, heat-treating the BAC solution to have a high HPLC peak 4, and then adding an acid at a low temperature, such as 50°C or lower. The double-activated BAC-Buffer solution may then be dried into a powdered form. [0028] The BAC may be aluminum chlorohydrate (ACH), aluminum sesquichlorohydrate (ASCH), or aluminum dichlorohydrate (ADCH). [0029] Heat-Activated and Acid-Activated BAC [0030] The BAC may be diluted and then heat-treated to form heat-activated ACH or ASCH at a temperature ranging from 80°C to 100°C for a time ranging from 8 to 16 hours. For example, the solution may be heated at 85°C for 10 hours. The solution may be cooled to a temperature, for example, ranging from 20 to 50°C. In some aspects, the cooling temperature may range from 30 to 35°C. [0031] Acid activation may be performed either simultaneously with heat activation or subsequent to the heat activation. Double activation is referred herein as being activated by both heat and acid. [0032] In one aspect, the heat-activated BAC may undergo acid addition to form double-activated ADCH (AACH) or double-activated ASCH (AASCH) in solutions that include a buffering agent and that have high HPLC peak 4 and peak 5. [0033] In some examples, ACH may be used as BAC. In such case, ACH may be first mixed with a first acid to produce ASCH with more depolymerized aluminum species. Then ASCH may be heated with water to produce heat-activated ASCH, and then heat-activated ASCH may be mixed with a second acid to produce AADCH, which is double-activated by heat and acid. These solutions containing double- activated ADCH or ASCH may be referred herein as AADCH-Buffer solution or AASCH-Buffer solution, respectively. In some aspects in which the buffer is glycine, these solutions may be AADCH-Glycine solution or AASCH-Glycine solution. In some aspects, the double-activated BAC-Buffer solution may have an HPLC peak 4, for example, of at least 20%, at least 30%, or at least 35% and below 65%, and may have an HPLC peak 5, for example, of at least 10%, at least 15%, or at least 20% and below 55%. [0034] The acid activation may preserve high HPLC peak 4 aluminum species and may generate more depolymerized aluminum species aluminum monomers and dimers, such that the double-activated aluminum species are produced. As described in connection with the indirect process, the acid addition may be performed at low temperature with a concentration of BAC solution ranging from, for example, 10% to 48% by weight. [0035] The double-activated BAC-Buffer solution may then be dried into a powder. The double- activated BAC-Buffer powders may be AASCH-Glycine powder or AADCH-Glycine powder. [0036] The aluminum salt may be represented by Chemical Formula 1: Al2(OH)6-aXa. “X” may be Cl or NO3. “a” may range between 1.0 to 6.6. For example, “a” may range from 1.2 to 2.2. Alternatively, “a” may range from 1.3 to 2.0 so that the Al/Cl molar ratio might range from 1 to 1.5.
GULBRA-009 [0037] The buffering agent may facilitate the activation of aluminum polymers to form high HPLC peak 4 aluminum species. The buffering agent may balance the pH of the double-activated BAC- Buffer solution with a stabilized peak 4, which improves its compatibility with an under-arm environment and improves formulation with enhanced efficacy. The buffering agent may also prevent aluminum species from further polymerization. [0038] The buffering agent may be a water-soluble amino acid. The amino acid includes, but not limited to, glycine, alanine, valine, arginine, etc. The other buffering agents can be betaine, urea, or a mixture thereof. In some aspects, the buffering agent is preferably glycine, which is shown in the examples to produce BAC salts with superior HPLC peak 4 and decreased acid loss during spray drying. The glycine concentration in the double-activated BAC salts may range from 1% to 25% by weight. This range depends on the Al/Cl ratio because the lower the Al/Cl mole ratio, the higher the amount the glycine is required. [0039] The acid may be HCl, HNO3, H2SO4, AlCl3, or Al(NO3)3. In some aspects, the acid is HCl, which is shown in the examples to demonstrate superior activation by keeping the HPLC peak 4 high. [0040] Preparation Through Indirect Method [0041] The indirect process may include thermally treating a BAC solution including acid and water at a temperature ranging from 80°C to 100°C and adding this solution to a second solution including acid, buffer, and water at a temperature below 50°C for a second acid activation. A temperature higher than 50°C may accelerate the degradation of HPLC peak 4. [0042] Specifically, under the indirect process, a double-activated BAC-Buffer solution may be created by adding an acid to a heat-activated BAC-Buffer solution to achieve a target Al/Cl mole ratio ranging from 1.71:1 to 2.0:1. During heat activation, water may be added to achieve a target aluminum concentration ranging from 0.74 to 3.75 (ranging from 2% to 10.02% Al in the feed solution) mole per kg aluminum concentration, such as 1.5 mole per kg aluminum concentration. The solution may be heated at a temperature ranging from 80°C to 100°C for a time ranging from 8 to 16 hours. For example, the solution may be heated at 85°C for 10 hours. The solution may be then cooled to a temperature, for example, ranging from 20 to 50°C. In some aspects, the cooling temperature may range from 30 to 35°C. The resulting solution includes heat-activated BAC and is referred to as Solution A or a variant thereof throughout the disclosure. [0043] A second solution may be prepared with HCl, water, and glycine with a target glycine strength ranging from 1.4 to 1.85 mole per kg glycine strength. The resulting solution is referred to as Solution B, which is a buffering solution with acid, or a variant thereof throughout the disclosure. [0044] Solution A and Solution B may then be comixed and agitated for 1 minute to 15 minutes, for example. In some aspects, the agitation time may be 2 minutes to 5 minutes. The comixing and agitation produces double-activated BAC-Buffer solution. This double-activated BAC-Buffer solution may be injected in a spray dryer to produce AADCH-Buffer powders or AASCH-Buffer powders. [0045] Preparation Through Direct Method
GULBRA-009 [0046] The direct method is a single step double activation process. The direct process may include simultaneous heat activation and acid activation by heat-treating a BAC solution including acid, buffer, and water. Specifically, the direct process may include adding acid to a BAC solution to achieve a target Al/Cl mole ratio ranging from 0.95:1 to 1.60:1. Water and buffer may be added to achieve a target aluminum concentration ranging from 1.18 to 3.85, such as approximately 1.5 mole per kg aluminum concentration. The solution may then be heat-treated at a temperature ranging from 85 to 100°C for a time ranging from 6 to 12 hours. For example, the solution may be heated at 85°C for 10 hours. [0047] Direct v. Indirect Method [0048] A double-activated BAC-Buffer solution prepared through the indirect process may have a higher HPLC peak 4 in comparison to a double-activated BAC-Buffer solution prepared through the direct process. The thermal treatment step in the direct process may destabilize HPLC peak 4 aluminum species in the double-activated BAC solution. In some aspects, an double-activated BAC-Buffer solution is prepared by the indirect process rather than by a direct process. [0049] Stability of the Stock Solution [0050] The HPLC peak 4 of the double-activated BAC-Buffer solution may decrease upon aging. The amount of buffering agent plays a role in producing a stable stock solution. If the glycine concentration is too high, the double-activated BAC-Buffer solution may gel or quickly form precipitates. To preserve both high HPLC peak 4 and peak 5, the double-activated BAC-Buffer solution may be dried to powdered form. [0051] Drying the Stock Solution [0052] The double-activated BAC-Buffer solution may be dried into a powder to preserve high HPLC peak 4 and peak 5. The stock solution may be spray dried, freeze dried, or drum dried into a powdered form. For example, the stock solution may be spray dried. The moisture content may be measured by loss on drying (LOD). For example, the LOD for the powder may be less than 13%, less than 11%, or less than 10%. [0053] Drying the stock solution is challenging because of the hygroscopic properties of the finished powders, i.e AADCH-Buffer powders and AASCH-Buffer powders at lower Al/Cl mole ratios. The moisture content of the AADCH-Buffer and AASCH-Buffer powders must be controlled to ensure that the powder is free flowing, does not agglomerate, and can be easily formulated into finished products. [0054] HPLC (Size Exclusion Chromatography) [0055] The degree of polymerization of aluminum complexes may be determined through size exclusion chromatography (SEC) operated via a high-performance liquid chromatography (HPLC) instrument. For this process, the highest molecular weight Al species may be eluted first and designated as peaks 1 and 2 (or Band I). Peaks 3 (or Band II) and 4 (or Band III) may indicate intermediate molecular weight Al complexes. Peak 5 (or Band IV) may indicate the lowest molecular weight Al complexes,
GULBRA-009 including monomers and dimers. The relative area of one or more peaks is determined to characterize the distribution of polymeric species in Al complexes. [0056] The double-activated BAC-Buffer solution may have an HPLC peak 4, for example, of at least 20%, at least 30%, or at least 35% and below 65%. Additionally, the activated BAC-Buffer solution may have an HPLC peak 5, for example, of at least 10%, at least 15%, or at least 20% and below 55%. [0057] Nuclear Magnetic Resonance Spectroscopy [0058]
27Al Nuclear Magnetic Resonance (NMR) may be used to identify the molecular structures of different aluminum species in the aluminum antiperspirant salts. The measurements may include the antiperspirant salt in solution form. The measurements may also include the powder form dissolved in deuterated water for a 5% by weight solution. Data may be collected using a Bruker AV-400 instrument at 104.2 MHz. [0059] A sharp peak at 0 ppm by
27Al NMR may indicate monomeric octahedral Al species. A peak at 4-5 ppm may indicate octahedral Al dimers. A sharp peak at about 63 ppm from a tetrahedral Al species may indicate Al species comprising one tetrahedral Al center. The other twelve octahedral Al centers in this compound may have peaks that are too broad to be detected. The broad peak at about 69-72 ppm may be due to HPLC peak 4 aluminum polymers. The double-activated BAC-Buffer solution of high efficacy may demonstrate a high amount of Al monomers at 0 ppm. [0060] Topical Compositions [0061] A topical composition including the double-activated BAC-Buffer powders may be in the form of liquid for a lotion, a cream, a soft-solid stick, a solid stick, or an aerosol. [0062] The composition may include inactive ingredients known in the art, including, but not limited to, cyclomethicone, behenyl alcohol, polypropylene glycol (PPG) 15 stearyl ether, isopropyl myristate, polyethylene, alkyl c12-15 benzoate, hydrogenated castor oil, talc, or colloidal silica. The composition may also include stearyl alcohol, dimethicone, sunflower oil, steareth 100, PEG-8, fragrance, mineral oil, or polyethylene glycol 400. [0063] To create an antiperspirant stick, the inactive ingredients may be mixed at a temperature ranging from 80°C to 85°C. The double-activated BAC-Buffer powders may be added in the bulk composition at a temperature ranging from 74°C to 80°C. The batch may be cooled to a temperature ranging from 65°C to 75°C. The cooled batch may be poured into molds and cooled further to approximately 50°C. EXAMPLES Example 1: Preparation AASCH-Glycine Powder by Indirect Process [0064] An AASCH solution was prepared by mixing a 50% ACH solution, HCl, and water to target an Al/Cl mole ratio of about 1.82:1 and approximately 1.5 mole per kg of Al strength. The diluted ASCH solution was heated to about 93°C and thermally treated for about 10 hours for activation to form Solution 1-A then cooled to 50°C. Solution 1-B was prepared by mixing HCl, water, and glycine for
GULBRA-009 approximately 1.41 mole per kg of glycine. Table 1 provides the weight for each component in Solution 1- A, and Table 2 provides the weight for each component in Solution 1-B.
more than 5 minutes, and the resultant solution was injected into the spray dryer to produce the double-activated ASCH- Glycine powder. The salt was micronized to a minimum 80% less than 10 microns particle size by the jet mill. Table 3 provides the properties of the AASCH-Glycine Powder. Table 3: Properties of AASCH-Glycine Powder Property Result Appearance Off-white powder pH (15% w/w aq. solution) 3.91 Aluminum 22.10% Chloride 19.48% Glycine 9.92% Al/Cl mole ratio 1.49:1 %Anhydrous 74.03% Iron (in PPM) 50 ppm % Peak 4 47.03 % Peak 5 23.73
GULBRA-009 Particle size (%<10um) 86.64% Example 2: AASCH-Glycine Powders [0066] Examples 2-I and 2-II were prepared according to the process in Example 1, except that the aluminum strength of the diluted AASCH solution (Solution 2-A) was maintained at 1.11 mole per kg in Example 2-I and at 1.30 mole per kg in Example 2-II, and the glycine strength was maintained at 1.85 mole per kg for Solution 2-B. Table 4: Preparation of Solution 2-A Component weight (kg) weight (kg) Example 2-I 2-II 50% ACH solution 27.99 23.92 Hydrochloric acid 1.12 0.96 Water 70.9 75.12 Total 100 100 Table 5: Preparation of Solution 2-B Component weight (kg) weight (kg) Example 2-I 2-II Water 71.73 71.73 AlCl3 11.23 11.23 Glycine 17.04 17.04 Total 100 100 [0067] Like in Example 1, Solution 2-A and Solution 2-B were co-mixed at below 50°C, and the resultant liquid was injected into the spray dryer to produce the AASCH-Glycine powders. To create an antiperspirant stick, the inactive ingredients may be mixed at a temperature ranging from 80°C to 85°C. Table 6 provides the properties of the AASCH-Glycine Powders. Table 6: Properties of AASCH-Glycine Powder Parameter Properties (2-I) Properties (2-II) Solution 2-A: Al mole/kg 1.30 1.11 Solution 2-B: Glycine 1.85 1.85 mole/kg Al/Cl mole ratio after co- 1.55:1 1.55:1 mixing
GULBRA-009 LOD (105°C/2 hours) 7.6% 8.4% Aluminum 22.13% 22.11% Chloride 18.15% 18.06% HPLC Peak 4 46.67% 52.30% HPLC Peak 5 25.56% 22.89% Al/Cl mole ratio 1.60:1 1.61:1 %Anhydrous 73.43% 73.32% [0068] As shown in Table 6, the lower the Al concentration of the feed solution (Solution 2-A), the higher the HPLC peak 4 of the resultant powder. Example 3: AASCH-Glycine Powders Produced from Different Acid Sources [0069] Examples 3-I and 3-II were prepared according to the process in Example 1, except that the aluminum strength of the diluted AASCH solution (Solution 3-A) was maintained at 1.67 mole per kg, and the acid was made by mixing polyaluminum chloride and HCl for an Al/Cl mole ratio of about 0.33 (Solution 3-B). Table 7: Preparation of Diluted AASCH solution (Solution- 3-A) Component Weight (kg) Weight (kg) Example 3-I 3-II 50% ACH solution 35.98 35.98 Hydrochloric acid 1.04 1.04 Water 62.97 62.97 Total 100.00 100.00 Table 8: Preparation of Solution 3-B Component Weight (kg) Weight (kg) Example 3-I 3-II Polyaluminum Chloride 13.91 - Hydrochloric acid 6.49 13.79 Glycine 15.47 16.38 Water 64.13 69.83 Total 100.00 100.00
GULBRA-009 [0070] Like in Example 1, Solution 3-A and Solution 3-B were co-mixed at below 50°C, and the resultant liquid was injected into the spray dryer to produce the double-activated ASCH-Glycine powder. Table 9 provides the properties of the AASCH-Glycine Powders. Table 9: Properties of AASCH-Glycine Powder Parameter Properties (3-I) Properties (3-II) Example 3-I 3-II LOD (105
OC/2 hours) 7.3% 8.1% Aluminum 22.87% 23.19% Chloride 18.32% 18.01% Glycine 9.66% 9.06% HPLC Peak 4 42.76% 46.26% HPLC Peak 5 17.46% 15.27% Al/Cl mole ratio 1.64:1 1.69:1 Anhydrous 75.66% 76.42% Example 4: Double-activated BAC-Glycine powders at different Al/Cl mole ratios [0071] Examples 4-I through 4-VV were prepared according to the process in Example 1. AASCH solutions (Solution 4-A) were used in combination with HCl*Buffer (Solution 4-B). Additionally, the aluminum strength of the resulting diluted AASCH solutions (Solution 4-A) were maintained at approximately 1.5 mole per kg, and the glycine strength was maintained at 0.25 to 0.35 mole per kg for the feed solutions of Solution 4-B. Table 10: Preparation of Solutions 4-A Example 50% ACH solution Hydrochloric Water Total Acid 4-I 32.2 0.8 67 100 4-II 32.2 0.8 67 100 4-III 32.2 0.8 67 100 4-IV 32.08 1.02 66.90 100 4-V 32.08 1.02 66.90 100 4-VI 32.73 0.89 66.39 100 4-VII 32.72 0.86 66.42 100
GULBRA-009 4-VIII 32.72 0.86 66.42 100 4-VIV 32.13 0.85 67.02 100 4-VV 32.73 0.87 66.40 100 Table 11: Preparation of Solutions 4-B Example Water Hydrochloric Glycine Total Acid 4-I 76.62 16.09 7.27 100 4-II 74.12 16.19 9.69 100 4-III 73.16 15.98 10.86 100 4-IV 73.16 15.98 10.86 100 4-V 73.12 15.43 11.45 100 4-VI 74.31 15.36 10.33 100 4-VII 72.41 14.97 12.62 100 4-VIII 74.23 15.35 10.42 100 4-VIV 69.85 13.03 17.11 100 4-VV 71.23 7.43 21.34 100 [0072] Solution 4-A and Solution 4-B were co-mixed at below 50°C, and the resultant liquids were injected into the spray dryer to produce the AASCH-Glycine and AADCH-Glycine Powders. Table 12 provides the properties of the AASCH-Glycine and AADCH-Glycine Powders. Table 12: Properties of AASCH-Glycine and AADCH-Glycine Powders Example Al/Cl mole ratio % Peak 4 % Peak 5 % Glycine Al/Cl mole ratio of the feed of the powder solution 4-I 0.85:1 30.60 48.07 14.49 1.03:1 4-II 1.14:1 41.37 33.55 14.65 1.21:1 4-III 1.18:1 42.49 30.92 14.68 1.25:1 4-IV 1.23:1 43.72 30.44 14.71 1.30:1 4-V 1.27:1 44.32 27.53 14.95 1.33:1
GULBRA-009 4-VI 1.42:1 47.82 22.08 9.38 1.48:1 4-VII 1.48:1 46.10 18.77 9.39 1.56:1 4-VIII 1.53:1 47.42 18.2 11.14 1.58:1 4-VIV 1.58:1 49.90 15.70 9.10 1.64:1 4-VV 1.68:1 50.47 12.88 8.39 1.74:1 [0073] As shown in Table 12, the higher the Al/Cl mole ratio, the higher the HPLC peak 4 and lower the HPLC peak 5 of the double-activated BAC-Glycine powders. Example 5: AADCH-Glycine Powders at Varying Glycine Contents [0074] Examples 5-I through 5-III were prepared according to the process in Example 1. The aluminum strength of the diluted AASCH solution (Solution 5-A) was maintained at 1.48 mole per kg with an Al/Cl mole ratio of 1.82:1. The glycine strength was maintained between 0.65 to 0.86 mole per kg (Solution 5-B). Table 13: Preparation of Solutions 5-A Example 50% ACH solution Hydrochloric Water Total Acid 5-I to 5-III 32.2 0.8 67 100 Table 14: Water Hydrochloric Glycine Total Preparation of Acid Solutions 5- BExample 5-I 77.81 16.34 5.85 100 5-II 79.74 15.45 4.81 100 5-III 78.30 16.00 5.69 100 [0075] Like in Example 1, Solution 5-A and Solution 5-B were co-mixed at below 50°C, and the resultant liquid was injected into the spray dryer to produce the double-activated ADCH-Glycine powder. Table 15 provides the properties of the AADCH-Glycine Powders. Table 15: Properties of AADCH-Glycine Powder
GULBRA-009 Example Al/Cl mole ratio of % Peak 4 % Peak 5 % Glycine Al/Cl ratio in co-mixing solution AADCH-Gly salt 5-I 0.85:1 30.6% 48.07% 14.49 1.03:1 5-II 0.89:1 31.3% 48.0% 16.00 1.00:1 5-III 0.88:1 31.9% 46.8% 17.40 1.03:1 [0076] As shown in Table 15, the data indicates that when the Al/Cl mole ratio is the same, a higher glycine content results in slightly increased HPLC peak 4 and a slightly decreased HPLC peak 5. Example 6: AADCH-Glycine powders made by targeting Al/Cl mole ratio 1.2:1 and 1.00:1 Table 16: Preparation of Solutions 6-A Example 50% ACH solution Hydrochloric Water Total Acid 6-I 32.20 0.80 67.0 100 6-II 32.02 1.02 66.97 100 6-III 32.08 1.02 66.90 100 Table 17: Preparation of Solutions 6-B Example Water Hydrochloric Glycine Total Acid 6-I 76.62 16.09 7.29 100 6-II 79.74 15.45 4.81 100 6-III 78.30 16.00 5.69 100 [0077] Examples 6-I through 6-III were prepared according to the process in Example 1. The aluminum strength of the diluted AASCH solution was maintained at 1.48 mole per kg (Solution 6-A). The glycine strength was maintained of 0.97, 0.64 and 0.76 mole per kg, respectively, for Examples 6-I through 6-III (Solution 6-B). Like in Example 1, Solution 6-A and Solution 6-B were co-mixed at below 50°C, and the resultant liquid was injected into the spray dryer to produce the double-activated ADCH-Glycine powder. Table 18 provides the properties of the AADCH-Glycine Powder. Table 18: Properties of AADCH-Glycine Powders
GULBRA-009 Exampl Al/Cl mole ratio % Peak 4 % Peak 5 % Glycine % Chloride Al/Cl mole e of the feed ratio of the solution powder 6-I 1.14:1 41.4% 33.55% 11.5 21.57 1.21:1 6-II 0.88:1 31.3% 48.81% 15.7 24.22 1.01:1 6-III 0.89:1 31.9% 48.03% 17.4 24.02 1.04:1 Example 7: Indirect v. Direct Process (AADCH-Glycine and AASCH-Glycine) Direct Process [0078] HCl was added to a 50% ACH solution under agitation and mixed for about 15 minutes to adjust the Al/Cl mole ratio. Subsequently, glycine and water were added to the mixture. The resultant solutions had aluminum concentrations ranging from 1.15 to 1.25 mole/kg. The resultant solutions were thermally treated at 93°C for about 10 hours for aluminum depolymerization. The resultant solution was then injected into the spray dryer to produce the AADCH-Glycine and AASCH-Glycine salts. Indirect Process [0079] Examples 7-I-Indirect through 7-V-Indirect were prepared according to the process in Example 1. The aluminum strength of the diluted and heat-activated ASCH solutions (Solution 7-A) were maintained at approximately 1.82:1 and 1.48 mol per kg. The glycine strength was varied in Solution 7-B to produce powders with different Al/Cl mole ratios. Like in Example 1, Solution 7-A and Solution 7-B were co-mixed, and the resultant liquid was injected into the spray dryer to produce the AASCH-Glycine powder. Table 19 provides the properties of the AASCH-Glycine Powder. Table 19: Preparation of Solutions 7-A and 7-B Solutions 7-A Solutions 7-B Exam 50% HCl Glycine Water Total Water HCl Glycine Total ple ACH soln. 7-I- 25.57 7.48 2.69 64.26 100 Not applicable Direct 7-I- 32.23 0.85 - 66.92 100 71.81 16.34 5.85 100 Indire ct
GULBRA-009 7-II - 27.88 5.04 2.75 64.34 100 Not applicable Direct 7-II - 32.23 0.85 - 66.92 100 76.62 16.09 7.29 100 Indire ct 7-III- 26.07 3.49 2.42 68.01 100 Not applicable Direct 7-III- 32.08 1.02 - 66.90 100 73.16 15.98 10.86 100 Indire ct 7-IV- 26.18 3.09 2.44 68.29 100 Not applicable Direct 7-IV- 32.08 1.02 - 66.90 100 73.12 15.43 11.45 100 Indire ct 7-V- 25.64 2.29 2.29 69.79 100 Not applicable Direct 7-V- 32.73 0.89 - 66.39 100 74.31 15.36 10.33 100 Indire ct 7-VI- 25.43 1.79 2.22 70.56 100 Not applicable Direct 7-VI- 32.72 0.86 - 66.42 100 74.23 15.35 10.42 100 Indire ct Table 20: Properties of AADCH-Glycine and AASCH-Glycine Powder Example Al/Cl ratio of %Peak 4 %Peak 5 %Glycine the Powder
GULBRA-009 7-I-Direct 1.02 14.79 52.29 14.60 7-I-Indirect 1.03 31.60 48.07 14.49 7-II -Direct 1.20 20.46 33.64 15.02 7-II -Indirect 1.21 41.37 33.55 11.50 7-III-Direct 1.31 23.44 28.72 14.41 7-III-Indirect 1.30 43.72 33.44 14.71 7-IV-Direct 1.36 24.10 24.85 14.93 7-IV-Indirect 1.33 44.32 27.53 14.35 7-V-Direct 1.47 26.78 18.89 14.13 7-V-Indirect 1.48 47.82 22.08 9.38 7-VI-Direct 1.59 33.42 15.12 14.61 7-VI-Indirect 1.58 47.42 18.2 11.14 [0080] As shown in Table 20, the indirect process results in AADCH-Glycine and AASCH- Glycine Powders with a much higher HPLC peak 4 than the powders prepared by direct process. [0081] Example 8: Indirect v. Direct Process (AADCH-Glycine and AASCH-Glycine) [0082] Preparation of Example 8-I (Indirect Process with Glycine) [0083] Example 8-I was prepared according to the process in Example 1. The aluminum strength of the diluted AASCH solution (Solution 8-I-A) was maintained at approximately 1.5 mole per kg with an Al/Cl ratio of 1.81:1. Solution 8-I-A was thermally treated at about 92°C for 12 hours. Solution 8-I-B had approximately 1.41 mole per kg of glycine in the solution and 1.36 mole per kg of HCl. Solution 8-I-A and Solution 8-I-B were co-mixed at below 50°C, and the resultant liquid was injected into the spray dryer to produce the AASCH-Glycine powder. [0084] Preparation of Example 8-II (Indirect Process without Glycine) [0085] Example 8-II was prepared according to the process in Example 1. The aluminum strength of the diluted AACH solution (Solution 8-II-A) was maintained at approximately 1.58 mole per kg with an Al/Cl ratio of 1.92:1. Solution 8-II-B was prepared with an approximately 22% w/w HCl solution instead of a HCl*Glycine solution. Solution 8-II-A and Solution 8-II-B were co-mixed at below 50°C, and the resultant liquid was injected into the spray dryer to produce the AASCH-Glycine powder. [0086] Preparation of Example 8-III (Direct Process without Glycine) [0087] Example 8-III was prepared according to the direct process in Example 7. The aluminum strength of the diluted AASCH solution was maintained at approximately 1.48 mole per kg and the Al/Cl
GULBRA-009 mole ratio was 1.42. Glycine was not used. The solution was also heated at 91°C for 11hours. The thermally treated solution was then injected into the spray dryer to produce the AASCH powder. [0088] Preparation of Example 8-IV (Direct Process with Glycine) [0089] Example 8-IV was prepared according to the process in Example 7 and the aluminum strength of the diluted AASCH solution was maintained at approximately 1.48 mole and glycine strength was 0.24 mol/kg. The solution was also maintained at 91°C for 14 hours. Like with the direct process in Example 7, the thermally treated solution was then injected into the spray dryer to produce AASCH- Glycine powder. [0090] Table 21: Properties of AASCH- Powder/AASCH-Buffer Powders 8-I 8-II 8-III 8-IV Example (Indirect process (Indirect process (Direct process (Direct Process with glycine) without glycine) without glycine) with Glycine) Mother solution (Al/Cl 1.81:1 1.92:1 1.42:1 1.42:1 mole ratio) Feed solution. (Al/Cl mole 1.42:1 1.42:1 - - ratio) % Peak 4 in feed soln. 51.8 47.33 41.06 26.24 % Peak 4 in powder 48.29 38.89 35.79 26.62 % Peak 5 in powder 21.44 26.41 27.26 24.0 Al/Cl mole ratio of the 1.47:1 1.65:1 1.62:1 1.49:1 powder %Aluminum 22.2 23.94 23.98 22.26 %Chloride 19.38 19.05 19.45 19.65 %Glycine 9.92 - - 9.81 Color b* of the powder 6.2 8.6 7.61 6.4 [0091] b*: values represent the color of the powder or salt by the level of yellowness or blueness in a test sample. The higher the b* yellower the powder. [0092] As shown in Table 21, AASCH-Glycine powders made through the indirect process are whitest, have the highest amount of HPLC peak 4, and demonstrate lowest chloride loss during spray drying.
GULBRA-009 [0093] Example 9: Effect of Buffer Type on AASCH-Buffer Powders at Al/Cl mole ratio 1.5:1 [0094] Examples 9-I through 9-III were prepared according to the process in Example 1, except that the Al/Cl mole ratio was 1.5:1 and that the buffers used were urea, arginine, or glycine. Table 22: Preparation of Solutions 9-A Component 9-I-A 9-II-A 9-III-A 50% ACH solution 32.73 28.09 31.71 Hydrochloric Acid 0.89 0.75 0.85 Water 66.39 71.16 67.44 Total 100 100 100 Table 23: Preparation of Solutions 9-B Component 9-I-B 9-II-B 9-III-B Water 74.31 73.70 73.72 Hydrochloric Acid 15.36 15.23 15.24 Glycine 10.33 – – Urea – 11.06 – Arginine – – 11.04 Total 100 100 100 Table 24: Properties of AASCH-Buffer Powder Component 9-I 9-II 9-III Type of Buffer Glycine Urea Arginine Aluminum 22.17% 21.89% 21.86% Chloride 19.66% 19.18% 19.11% Glycine 9.38% – – Urea – 8.79% – Arginine – – 9% Al/Cl mole ratio 1.48:1 1.50:1 1.50:1 % Peak 4 47.82% 52.94% 50.48%
GULBRA-009
Example 10 Comparison AADCH-Glycine Powders Made from HCl vs. AlCl
3 [0095] Examples 10-I through 10-III were prepared according to the process in Example 1, except that the aluminum strength of the diluted AASCH solution (Solution 10-A) was maintained at 1.46 mole per kg with an Al/Cl ratio of 1.82, and the glycine strength was maintained at 2.75 mole per kg (Solution 3-B). Table 25: Preparation of Solutions 10-A Component 10-I-A 10-II-A 50% ACH solution 32.47 32.22 Hydrochloric Acid 0.87 0.78 Water 66.67 67.00 Total 100 100 Table 26: Preparation of Solutions 10-B Component 10-I-B 10-II-B Water 77.88 46.24 Glycine 7.22 20.88 Hydrochloric Acid 14.90 — AlCl3 (28% anhydrous-aq. soln) — 32.88 Total 100 100 [0096] Solution 10-A and Solution 10-B were co-mixed, and the resultant liquid was injected into the spray dryer to produce the double-activated ADCH-Glycine powder. Table 27 provides the properties of the powders. Table 27: Properties of the AADCH-Glycine Powders Parameters %LOD %Al %Cl %Glyci Al/Cl %Anhydro %Peak 4 %Peak 5 ne mole ratio us 10-I 10.16 19.24 21.79 17.61 1.16:1 66.97 39.26 40.45 10-II 9.25 19.70 22.04 16.65 1.17:1 68.43 33.80 39.29 [0097] As shown in Table 27, the data indicates that HCl*Glycine has better activation effect than AlCl3*Glycine. [0098] Preparation of Antiperspirant Sticks
GULBRA-009 [0099] The ingredients in Table 27 were mixed in a stainless-steel vessel at a temperature ranging from 80°C to 85°C. The powders from Example 1 were added in the bulk composition at a temperature ranging from 74°C to 80°C and mixed. Mixing was continued, and the batch was subjected to a cooling to a temperature ranging from 65°C to 75°C. The hot contents were poured into molds. Solid antiperspirant sticks, with uniform and random orientation of crystals, were obtained upon cooling below approximately 50°C. Table 28: Contents of Antiperspirant Sticks Ingredients Quantity Cyclomethicone QS to 100 g Behenyl alcohol 14.00 g PPG 15 stearyl ether 9.00 g Isopropyl myristate 6.00 g Alkyl C12-15 benzoate 3.00 g Polyethylene and 6.72 g Hydrogenated castor oil Talc 2.50 g Colloidal silica 1.50 g Example 10-I or 10-II 27.10 gm (~20% anhydrous solid content) Table 29: Stick Formulation Parameters Appearance Solid stick Color White to off white Avg % Chloride content 5.25 ± 0.15 gm Penetration value - 7.0 ± 0.5 mm < 12 mm Freezing point - 62 to - 66
°C Softening point 53 to 56
°C Stability at 45
°C, 75% RH 30 days - Stable Example 11: Hot Room Back Testing [00100] Preparation of AASCH-Ca-Glycine [00101] 50% ACH solution was mixed with HCl to achieve an Al/Cl mole ratio of 1.70:1. Water, calcium chloride dihydrate (CaCl2*2H2O), and glycine were added to the AASCH solution, and the
GULBRA-009 resulting solution was agitated for 30 minutes until a clear solution was obtained. The solution was thermally treated at 92°C for 3 hours. The resulting hot solution was injected into a spray dryer to produce the AASCH-Ca-Glycine powder. The dried powder was micronized into the jet mill to the desired particle size of minimum 80% less than 10µm. [00102] Preparation of AADCH-Glycine Powder [00103] An AADCH solution was prepared by mixing an ACH solution with HCl followed by 15 minutes of agitation for an Al/Cl mole ratio of 1.82:1. Water was added and the solution was agitated for 15 minutes at 300 rpm. The resulting solution contained an aluminum strength of 1.46 mole per kg. The resulting solution was thermally treated at 90°C for 11 hrs. This solution was referred to as Solution 10-A. [00104] A HCl*Glycine solution was having 0.13 molar chloride strength. Glycine was added to the solution and was agitated for 20 minutes until a clear solution was obtained and designated as Solution 10-B. [00105] 62. 5 g Solution 10-A and 37.5 g Solution 10-B were mixed in-line at below 50°C. The resulting solution was injected into a spray dryer to produce the AADCH-Glycine powder. The dried powder was micronized into the jet mill to the particle size of 80% under 10 µm. [00106] To test the efficacy, a 72-hour antiperspirant efficacy test was conducted by measuring the relative reduction of sweating compared to untreated control areas under dermatological control. The study was performed on a panel of female subjects with healthy skin in test areas located on the back of the subjects. For the test products, Powders A and B were dissolved in aqueous solution to achieve the same % anhydrous solids. Test products were applied under occlusive conditions to the test areas on four consecutive days.72 hours after product application, pre-weighed pads were fixed to the test areas before the subjects entered a sauna for approximately 15 minutes to induce sweating. Afterwards, the amount of sweat was determined gravimetrically. Each test product was compared to a corresponding untreated area located on the contralateral site of each subject’s back. [00107] The study included 23 subjects. The study included untreated control areas and subjects with no treatment on their backs. Furthermore, test areas were assigned by cyclic permutation. [00108] Day 1 (start of test phase): Randomized subjects had the test product applied on the test area on their back. The subjects then rested for approximately five minutes so that the test products could be absorbed into the skin. The test area was then covered with the patch test system and then removed 2 hours (± 5 minutes) after application by a lab technician. [00109] Days 2 to 4 (test phase): Subjects came to the study site. Subjects waited at least 10 minutes before product application. Afterwards, the subjects repeated the method described in connection with Day 1. [00110] Days 6 and 7 - 72 hours after application (test phase): Subjects came to the study site. The back of the subjects was cleaned with water and dried with a paper towel. Before the sweat collection
GULBRA-009 period, the absorbent pads were weighed in a cup under standard room conditions. The test areas and untreated contralateral areas were covered with the absorbent pads, which were attached to the back with the patch test system. The subjects then laid down in a sauna at a temperature of approximately 80°C for about 15 minutes. Afterwards, the absorbent pads were removed from the patch test system with tweezers and immediately re-weighed under standard room conditions. The difference between the two gravimetric measurements represents the absorbed sweat weight. There was one measurement per test area and per assessment time. The raw data of the container including the absorbent pad weight before and after sweating (in grams) was recorded for each treated and untreated control area. [00111] Analysis of data: The amount of sweat at each treated and untreated control area was calculated as the difference between the absorbent pad weight before and after sweating. Further, the relative sweat reduction [%] was computed as the percentage quotient of sweat amount at treated over untreated areas for each treatment. Relative sweat reduction is considered as valid if sweat amount at the treated and/or corresponding untreated control area was ≥ -0.005 g. [00112] Treatment comparison was performed on relative sweat reduction after removal of invalid data, non-responders, and outliers using paired t-test. Comparison of treated and untreated areas as performed with the one sample t-Test versus 0% per treatment code for relative sweat reduction after removal of invalid values, non-responders, and outliers. The computation of the statistical data was carried out with a commercially available statistics software (SAS for Windows). The results are presented in Table 30. Table 30: Hot Room Backtesting Results Parameter AADCH-Glycine AASCH-Ca-Glycine Aluminum (%) 18.3 19.32 Chloride (%) 23.69 19.83 Calcium (%) – 2.95 Glycine (%) 17.48 16.5 Al/Cl mole ratio 1.02:1 1.74:1 Anhydrous Solids (A.S%) 65.24 63.46 HPLC Peak 1+2 (%) 0.55 0.71 HPLC Peak 4 (%) 31.67 75.2 HPLC Peak 5 (%) 50.29 4.53
GULBRA-009 Sweat Reduction (%) by 66.32 54.00 Back Testing after 72 hr [00113] As shown in Table 30, AADCH-Glycine showed 22.8% better sweat reduction after 72 hours compared to sample AASCH-Ca-Glycine.