What is the solubility challenge?

葡甲胺 : 功能性增溶剂

Permeability 90% Introduction What is the solubility challenge? Biopharmaceutical Classification System (BCS): Class II 70% Class I 5% About 90% of all NCEs show poor solubility Class IV 20% Class III 5% 2 0.1mg/ml Solubility Benet, EDAN, Leuven, March 18-20 2007

Introduction Approaches to overcome poor solubility Drug substance Formulation Chemical Physical Surfactants API modif. Cosolvents Salts Solid Solutions Solvates Drug Delivery Technology Particle size Complexation Overlapping! 3

Counter-Ions Introduction 5 Issue: Solubility and dissolution rate of salt >> free acid/bases Target segment: bioavailability enhancement of BCS Class II compounds (low solubility, high permeability) Salt selection criteria pk a ( 3 units difference between ionizable part of drug and counter-ion [1]; 2 also acceptable [2]) Toxicity Stability Polymorphism Crystallinity Hygroscopicity ph-dependency of the dissolution rate Ease of synthesis Processability into final dosage form Costs References: 1. Bowker MJ, Stahl PH (2008) Preparation of water soluble compounds through salt formation. In: Wermuth CG (ed) The practice of medicinal chemistry. Academic, New York, p 749 2. Hughey, JR, Williams III, RO (2012) Solid-State Techniques for Improving Solubility. In: R.O. Williams III et al. (eds.), Formulating Poorly Water Soluble Drugs. Springere, New York, pp. 95-131

Insert: What is a pk a value? pk a values are used to classify the acidity of chemical compounds The smaller the value, the stronger is the acid Substance Hydrochloric acid Acetic acid pk a - 8.0 strong acid 4.75 weak acid Ammonia 38 base 6

Counter-Ions 改善难溶性药物的溶出, 提高生物利用度 Meglumine 高效助溶剂葡甲胺 Ph.Eur: Megluminum; USP: Meglumine 1-Deoxy-1-(methylamino)-D-glucitol, 1-Deoxy-1-methylaminosorbitol; N-Methyl-d-glucamine Sorbitol derivative, amino group pk a = 8.03 suitable for ionizable compounds pk a < 6.0 physiological conditions: protonated form 7

Application range of meglumine Application fields for meglumine A) As an advanced intermediate/ API Salt of meglumine and the active is applied Meglumine has to be considered as part of the API B) As a functional excipient ph modifier Alkalizer Stabilizer A complex with the active is formed in the body Meglumine has to be considered as part of the API C) In the biological sector Stabilization of proteins: antibodies, peptides Use of API grade is mandatory Use of API grade is strongly recommended Use of API grade is recommended 8

Current customers/applications Imaging Products Excipients 9

Meglumine as a functional excipient: Improves dissolution rate and solubility (1) Application of meglumine as a functional excipient improves the dissolution profile of poorly water-soluble drug glipizide (pk a 5.9) 格列吡嗪 Meg1: 1% meglumine Meg2: 2% meglumine Meg3: 3% meglumine Tested system: Osmotic pump tablets. Drug release is directly dependent on the drug solubility and permeability of the membrane (semi-permeable coating) Testing conditions: USP II apparatus (paddle) 900 ml phosphate buffer ph 6.8 50 rpm 10 1 Merck Millipore: Meglumine - A solution to enhance the bioavailability and stability of your APIs Source: Mehramizi, A., B. Alijani, et al. (2007). "Solid Carriers for Improved Solubility of Glipizide in Osmotically Controlled Oral Drug Delivery System." Drug Development and Industrial Pharmacy 33(8): 812-823.

Meglumine as a functional excipient: Improves dissolution rate and solubility (2) Application of meglumine as a functional excipient improves the dissolution profile of poorly water-soluble drug telmisartan (pk a 4.5) 替米沙坦 Tested system: spray-granulated tablets Testing conditions: USP II apparatus (paddle) 900 ml phosphate buffer ph 7.5 75 rpm Reference = Originator (Micardis, Boehringer Ingelheim; contains meglumine) 11 Data extracted from: Parikh, B. N., D. M. Patel, et al. (2010). "Formulation, optimization and evaluation of immediate Merck Millipore: Meglumine - A solution to enhance the bioavailability and stability of your APIs release tablet of telmisartan." Journal of Global Pharma Technology 2(2).

Choice of the counter-ion The pk a value of the counter-ion is crucial: A difference of 2-3 units is required, otherwise, no salt with the drug substance will be formed For which actives may meglumine be used as a counter-ion? pk a value of meglumine = 8.03 Meglumine is suitable for actives with a pk a value of 6 or less 12

13 适用于葡甲胺的难溶性药物

适用于葡甲胺的难溶性药物 2011 年销售额阿托伐他订缬沙坦埃索美拉唑孟鲁司特阿莫西林奥美拉唑辛伐他汀双氯芬酸坎地沙坦泮托拉唑 98 亿欧元 62 亿欧元 59 亿欧元 46 亿欧元 32 亿欧元 32 亿欧元 30 亿欧元 26 亿欧元 25 亿欧元 25 亿欧元氯沙坦 23 亿欧元兰索拉唑 22 亿欧元替米沙坦 19 亿欧元布洛芬 19 亿欧元厄贝沙坦 19 亿欧元雷贝拉唑 18 亿欧元阿仑磷酸 10 亿欧元普伐他汀 8 亿欧元瑞格列奈 4 亿欧元以及更多 pka 值小于 6 的药物! 14 蓝色部分为专利即将过期或近期已过期的药物

Why API quality? Consequence from FDA and EMEA statements: The manufacture of an API is performed according to ICH Q7 The manufacture of the counter-ion has to be performed according to ICH Q7 Consequently, the counter-ion MUST be considered as part of the API According to the FDA, different salt forms of a drug substance MUST be considered as different APIs The same is recommended for the application as a functional excipient, as a complex with the active is formed in the body. 15

Where to get API grade meglumine? Parameter Shanghai Local Supplier Merck Benefit Grade CP USP, EP, JP, IDL Suitable for both domestic and oversea markets Melting point Specific rotation Absorbance of solution 128-132 centigrade -15.5 to -17.5 degree No data 128-131 centigrade (fix value on CoA) -16.0 to -17.0 degree We give a fixed value in the CoA rather than a range as indicated by the competitors. This indicates that our product has a sharp melting point which is mainly due to ver y low imputiry content. Higher the impurity content, broader the melting range. A narrower range of specific rotation again indicates that our product has a lower impurity content Absorbance is A detailed UV-visible aborbance data is useful for more accurate characteriztion of described clearly for the material UV & visible range Chloride No data 90ppm Customer would prefer a specific data for this parameter rather than no limit Cyanide No data 2ppm Customer would prefer a specific data for this parameter rather than no limit Arsenic No data 1ppm Customer would prefer a specific description for heavy metal content Al No data 5ppm Customer would prefer a specific description for heavy metal content Iron No data 10ppm Customer would prefer a specific description for heavy metal content Loss on drying (105) Bacterial endotoxin 0.5% Max 0.2% Max complies 1.5 IU/g Methanol (GC) No data 0.2% Max Our LOD value is extremely low. A higher value of LOD indicates high residual solvent/water content. A clear description of BE level that this material can be safely used even for parenteral application 16

Comparative study (exemplary results) Test Appearance of solution Ph. Eur., USP, JP Pharmacopoeia MM specification Clear, colorless typical MM results Clear, colorless Competitor** results Almost clear, yellow Absorbance at 350nm* - 0.200 <0.020 2.780 (139x) Absorbance at 400nm* - 0.100 <0.005 0.981 (196x) Absorbance at 450nm* - 0.080 <0.0005 0.439 (878x) Absorbance at 420nm* Ph. Eur., USP 0.045 < 0.045 0.142 (3x) Aluminium Ph. Eur. 0.0005% 0.0002% 0.0011% (6x) Interpretation of results 大量不明确的有关物质 Competitor sample does not meet Ph.Eur., USP and JP limits! Competitor sample does not meet Ph.Eur. limits! Nickel Ph. Eur.**** 0.0005% 0.0001% 0.0009% (9x) 对照品不符合中国药典要求! * Absorbance was measured with a 30% (m/v) solution of meglumine in water *** Competitor claims material is of pharmaceutical quality and corresponds to CP/BP (no ICH Q7 quality). *** 存在毒性物质 : 某些美拉德反应的产品被报道具有致癌作用, 并与老年痴呆症和二型糖尿病有关 ; 并且, 他们还可能与主药反应, 影响制剂的稳定性 **** Limits for elemental impurities are published in USP 35 (December 2012) and will be enforced in May 2014 17 Merck Millipore: Meglumine - A solution to enhance the bioavailability and stability of your APIs