诺华制药资料：药物成盐的原理、策略和知识产权保护
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− pKa 1.8 – 2.2 (triazole antifungal agents of the α-styrylcarbinol) − Crystalline HCl salt (pKa -6.1): 12% loss of chloride after 6 hrs at 60ºC − Crystalline mesylate salt (pKa -1.2): stable after 3 weeks storage at 60ºC
Salt Screening and Selection:
New Challenges and Considerations in the Modern Pharmaceutical R&D Paradigm
Wei-Qin (Tony) Tong, Ph.D.
Novartis Pharmaceuticals Corporation Integrated Drug Product Development Process (3 day-course), University of Utah July 17-19, 2006
Solubility and Dissolution Rate of Salts
• Intrinsic dissolution rate of bupivacaine and its HCl salt as a function of the pH of the dissolution medium
Impact of Salts
• Impact on pharmaceutical properties required for a successful dosage form: − bioavailability − stability (both chemical and physical) − manufacturability • Impact on physicochemical properties of the drug substance: − Solubility − Dissolution rate − hygroscopicity − Chemical stability − Crystal form − Mechanical properties
Precipitate as HCl salt (crystalline or amorphous)
Dissolve or convert to free base and dissolve Dissolve or convert to free base and dissolve
Ref: Tong W.Q. and Whitesell G., Pharm. Dev. Tech., 3, 215-223, (1998). Marra-Feil M. and Anderson B.D., PharSci., 1, S-400, (1998).
Solubility and Dissolution Rate of Salts
Solid Phase: Base
pH
Ref: Serajuddin & Pudipeddi, in Handbook of Pharmaceutical Salts , IUPAC, 2002 Salts,
The Role of pKa
• For stable salt formation to be complete, ionization must be effectively complete such that a single ionization state is form. • 2 pH units difference between the pKas of the base and the acid typically necessary • With counter ions that correspond to volatile acids or bases, the pKa requirement may be different, e.g.
• Success rate has not improved. • Competition is intensifying:
− Faster to market and protection of intellectual properties are becoming a necessity
New Challenges for Development Scientists: how do these challenges affect salt screening and selection? • Consideration of pharmaceutical properties in drug design - developability assessment: Need to consider the impact of salts on developability • Shorter development timeline: Need to select the right salt the first time • Increased need for special drug delivery systems: Need to evaluate the impact of salts on the solubility and stability in these systems
Ref: Pudipeddi et. al, in Handbook of Pharmaceutical Salts, IUPA C, 2002, IUPAC, Original ref: Shah J.C. and Maniar J., J. Contr. Rel., 23, 261 -270, (1993). 261-
Solubility Product and In Situ Salt Screening
• If free base is added to a certain concentration of acid, with the acid concentration high enough to ensure the pH of the solution is lower than pHmax, the base will form the corresponding salt with the acid. • The solubility product (Ksp) and the solubility of the salt formed in situ can be calculated. • Multiple counter-ions, added in predetermined amounts so as not to exceed the Ksp of any salt, can provide significantly higher solubility than single counter-ion.
• It is only at a pH value less than pHmax that the solubility of the salt can be determined • Saturated solution in the presence of buffer species: salt conversion may occur • Effect of solubility and microenvironment pH on dissolution rate: self-buffering effect
− > 40% compounds belong to class II and IV (FDA biopharmaceutical classification system)
• Gap between Research and Development is disappearing:
− Profiling of pharmaceutical properties of drug candidates becomes a routine practice
Dissolution Process of the Salt of Basic Drugs
Dissolved Drug
Remain in solution
Dissolved Drug
salt of an basic drug
Precipitate as free base (crystalline or amorphous)
Presentation Outline
• Introduction • Theoretical Considerations
• • • • • • • • • • • •
pH-solubility profiles, pKa and salt formation Prediction of salt solubility Solubility product and in situ salt screening Solubility/dissolution rate of salts Dissolution of salts in the GI fluids Salts and other solubilization techniques Effect of salts on chemical stability Dosage form considerations Toxicity considerations Salt and form selection strategies Impact of salt on intellectual property (IP) and life cycle management (LCM) Automation and high throughout
“Changing the salt, changing the drug”
Theoretical Consideratwenku.baidu.comons
pH-Solubility Profile
Solubility of salt
Monobasic Compound
pHmax
Solubility
Solubility of free base Solid Phase: Salt
Prediction of Salt Solubility
• Contributing factors to salt solubility: − solvation energy/heat of solvation − crystallinity/heat of fusion • Solubility of salts are still largely unpredictable except for some general trends • Most of the empirical methods requires melting point that is difficult to obtain without making the actual salt
• Practical Considerations
• Case Studies • Summary
Introduction
Modern R&D Paradigm
• Combinatorial chemistry and high-throughput screening result in many more hits and more development candidates. • Properties of NCEs become less favorable for development:
Salt Screening and Selection:
New Challenges and Considerations in the Modern Pharmaceutical R&D Paradigm
Wei-Qin (Tony) Tong, Ph.D.
Novartis Pharmaceuticals Corporation Integrated Drug Product Development Process (3 day-course), University of Utah July 17-19, 2006
Solubility and Dissolution Rate of Salts
• Intrinsic dissolution rate of bupivacaine and its HCl salt as a function of the pH of the dissolution medium
Impact of Salts
• Impact on pharmaceutical properties required for a successful dosage form: − bioavailability − stability (both chemical and physical) − manufacturability • Impact on physicochemical properties of the drug substance: − Solubility − Dissolution rate − hygroscopicity − Chemical stability − Crystal form − Mechanical properties
Precipitate as HCl salt (crystalline or amorphous)
Dissolve or convert to free base and dissolve Dissolve or convert to free base and dissolve
Ref: Tong W.Q. and Whitesell G., Pharm. Dev. Tech., 3, 215-223, (1998). Marra-Feil M. and Anderson B.D., PharSci., 1, S-400, (1998).
Solubility and Dissolution Rate of Salts
Solid Phase: Base
pH
Ref: Serajuddin & Pudipeddi, in Handbook of Pharmaceutical Salts , IUPAC, 2002 Salts,
The Role of pKa
• For stable salt formation to be complete, ionization must be effectively complete such that a single ionization state is form. • 2 pH units difference between the pKas of the base and the acid typically necessary • With counter ions that correspond to volatile acids or bases, the pKa requirement may be different, e.g.
• Success rate has not improved. • Competition is intensifying:
− Faster to market and protection of intellectual properties are becoming a necessity
New Challenges for Development Scientists: how do these challenges affect salt screening and selection? • Consideration of pharmaceutical properties in drug design - developability assessment: Need to consider the impact of salts on developability • Shorter development timeline: Need to select the right salt the first time • Increased need for special drug delivery systems: Need to evaluate the impact of salts on the solubility and stability in these systems
Ref: Pudipeddi et. al, in Handbook of Pharmaceutical Salts, IUPA C, 2002, IUPAC, Original ref: Shah J.C. and Maniar J., J. Contr. Rel., 23, 261 -270, (1993). 261-
Solubility Product and In Situ Salt Screening
• If free base is added to a certain concentration of acid, with the acid concentration high enough to ensure the pH of the solution is lower than pHmax, the base will form the corresponding salt with the acid. • The solubility product (Ksp) and the solubility of the salt formed in situ can be calculated. • Multiple counter-ions, added in predetermined amounts so as not to exceed the Ksp of any salt, can provide significantly higher solubility than single counter-ion.
• It is only at a pH value less than pHmax that the solubility of the salt can be determined • Saturated solution in the presence of buffer species: salt conversion may occur • Effect of solubility and microenvironment pH on dissolution rate: self-buffering effect
− > 40% compounds belong to class II and IV (FDA biopharmaceutical classification system)
• Gap between Research and Development is disappearing:
− Profiling of pharmaceutical properties of drug candidates becomes a routine practice
Dissolution Process of the Salt of Basic Drugs
Dissolved Drug
Remain in solution
Dissolved Drug
salt of an basic drug
Precipitate as free base (crystalline or amorphous)
Presentation Outline
• Introduction • Theoretical Considerations
• • • • • • • • • • • •
pH-solubility profiles, pKa and salt formation Prediction of salt solubility Solubility product and in situ salt screening Solubility/dissolution rate of salts Dissolution of salts in the GI fluids Salts and other solubilization techniques Effect of salts on chemical stability Dosage form considerations Toxicity considerations Salt and form selection strategies Impact of salt on intellectual property (IP) and life cycle management (LCM) Automation and high throughout
“Changing the salt, changing the drug”
Theoretical Consideratwenku.baidu.comons
pH-Solubility Profile
Solubility of salt
Monobasic Compound
pHmax
Solubility
Solubility of free base Solid Phase: Salt
Prediction of Salt Solubility
• Contributing factors to salt solubility: − solvation energy/heat of solvation − crystallinity/heat of fusion • Solubility of salts are still largely unpredictable except for some general trends • Most of the empirical methods requires melting point that is difficult to obtain without making the actual salt
• Practical Considerations
• Case Studies • Summary
Introduction
Modern R&D Paradigm
• Combinatorial chemistry and high-throughput screening result in many more hits and more development candidates. • Properties of NCEs become less favorable for development: