Polymorphism: opportunity or problem?
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The document discusses the significance of polymorphism in active pharmaceutical ingredients (APIs), identifying various types and their implications for drug development and patentability. It highlights the impact of drug forms on properties such as solubility, stability, and manufacturability, while noting that 85% of APIs exhibit pseudo-polymorphism. Additionally, the paper examines factors affecting polymorphism and provides examples of conversions between crystal forms, emphasizing the importance of controlling polymorphic forms in pharmaceutical formulations.
Polymorphism: opportunity or problem?
- 2. www.polycrystalline.it • What is APIs polymorphism? • What is the impact of polymorphism? • Disappearing polymorphs • What are the factors that can affect polymorphism? • Conclusions Contents
- 4. www.polycrystalline.it TYPES OF POLYMORPHS: FOR THE SCIENTIST 4 CONCOMITANT POLYMORPHS: the appearance of two or more polymorphs within the same crystal batch. CONFORMATIONAL POLYMORPHS: the same molecule can adopt different crystal shapes in different crystals due to internal degrees of freedom. SOLVATES AND POLYMORPHIC SOLVATES: occur when a given substance crystallizes with different amounts or types of solvent molecules. The packing of a molecule can be arranged in many ways in the crystal in a given symmetry and polymorphism is a reflection of alternative ways in which molecules in a crystal strive towards a free energy minimum.
- 5. www.polycrystalline.it TYPES OF POLYMORPHS: FOR THE REGULATOR 5 The International Conference on Harmonization (ICH) Guideline Q6A specifications for new drug substances and products (October 1999) “polymorphism” includes: Single entity POLYMORPHS Molecular adducts (solvates/hydrates) Amorphous forms PSEUDO-POLYMORPHS
- 6. www.polycrystalline.it SOLID CRYSTALLINE AMORPHOUS Long range order Short range order Multi components POLYMORPHS Single component Ionic Non-ionic SALT MOLECULAR ADDUCTS SOLVATE/HYDRATE CO-CRYSTAL Molecule solid at RT Free drug Protonated drug molecule Deprotonated acid TYPES OF POLYMORPHS: SUMMARY 6 Solvent PSEUDO- POLYMORPHS
- 7. www.polycrystalline.it WHAT IS THE IMPACT OF POLYMORPHISM?
- 8. www.polycrystalline.it WHAT IS THE IMPACT OF POLYMORPHISM? 8 A critical element of drug discovery and the early stages of drug development is the identification of the appropriate drug form. Drug form refers to the nature of the solid drug entity (free acid, free base, salt or non ionisable compound) and additionally to its solid state (amorphous, crystalline and polymorphic phase). Statistically, 85% APIs exhibit pseudo-polymorphism, and 50% of APIs have multiple forms.
- 9. www.polycrystalline.it The drug form impacts on different properties, such as: Spectral Properties Solubility, Bioavailability & Dissolution Rate Physical and Chemical Stability Manufacturability Hygroscopicity Crystal Shape WHAT IS THE IMPACT OF POLYMORPHISM? 9
- 10. www.polycrystalline.it By definition, every new crystal form is novel and IS NOT POSSIBLE TO PREDICT: • How MANY different crystal forms can be prepared • How to PREPARE any, as yet unknown, crystal forms • The PROPERTIES of any, as yet unknown, crystal forms Therefore, new or additional crystal forms can be patented in order to: • PROTECT the drug substance from use by competitors • AVOID infringing a patent PATENTABILITY OF CRYSTAL FORMS 10 Merck’s Fosamax® (Alendronate) Its sales in 2002 were $2.2 billion What happened? Generic version with a different crystalline form was launched by Teva Pharmaceutical before Merck’s patent expiration.
- 11. www.polycrystalline.it WHAT ARE THE FACTORS THAT CAN AFFECT POLYMORPHISM?
- 12. www.polycrystalline.it FACTORS AFFECTING POLYMORPHISM 12 Many drugs undergo polymorphic transformation during various processes, such as: TEMPERATURE AND HUMIDITY: Storage conditions affect physicochemical reactions which are accelerated at higher temperature. Humidity act as catalyst on the solid surface. PHOTOSTABILITY: Generally light sensitive drugs are protected from the photolytic degradation by packing them suitably in light resistant container. SOLVENT: Solvent can bring dramatic change in growth mechanism and morphology.
- 13. www.polycrystalline.it FACTORS AFFECTING POLYMORPHISM 13 GRINDING: During grinding process solid state polymorphic transformation into non-crystalline or metastable form is caused by mechanical action. SURFACTANT: Surfactant affect solution mediated transformation of the drug which depends on molecular and supramolecular structure of the drug. COMPRESSION: Stability and compaction behavior form of the polymorphic form of drug is important. Many drugs undergo polymorphic transformation during various processes, such as:
- 14. www.polycrystalline.it EXAMPLES OF CONVERSIONS BETWEEN FORMS 14 Conversions between crystal forms are possible and often take place. Among the many possibilities for conversion, specific examples are: An anhydrous crystalline form can be transformed into a crystal hydrate via vapour uptake from the atmosphere. A metastable crystalline form can convert into a thermodynamically more stable crystal over time. An unsolvated crystal form can form solvates and co-crystals with other molecules.
- 16. www.polycrystalline.it DISAPPEARING POLYMORPHS 16 When a compound exhibits polymorphism the existence of more than one crystal structure it may be important to obtain a particular polymorph under controlled and reproducible conditions. There are cases where it was difficult to obtain a given polymorphic form even though this had previously been obtained routinely over long time periods. WHERE IS MY FORM? The worst that can happen for a pharmaceutical company is if a new polymorph suddenly appears in the temperature and humidity conditions of a blister pack when a compound is actually on the market.
- 17. www.polycrystalline.it WHEN DRUGS GO BAD: THE RITONAVIR STORY 17 Ritonavir was patented in 1993 and marketed in 1996 by Abbott Laboratories. The drug was on the market for 18 months before a serious problem emerged: the drug began precipitating out of formulation in large quantities. The new form was dubbed Form 2 and was found to be less soluble, greatly reducing bioavailability. Abbott was forced to remove Ritonavir from the market until they solved the problem, resulting in extreme losses: • More than $250 million in sales • Estimated hundreds of millions of dollars in R&D trying to recover the original Form 1 What happened?
- 19. www.polycrystalline.it WHAT IS THE NEED TO STUDY POLYMORPHISM? 19 • Each solid form of a pharmaceutical can be patented. It is, then, critically important that the company developing the drug knows all the forms in order to secure intellectual property. • The knowledge of solid-state properties in an early stage of drug development helps to avoid manufacturing problems, to fine-tune the performance of drugs and provides space for innovations. • Improve the therapeutic activity of drugs. • Better bioavailability of drugs.
- 20. www.polycrystalline.it We support our clients from early-phase to kilogram supply. DISCOVER DESIGN DETERMINE DEVELOP HOW CAN WE HELP YOU? 20
- 21. www.polycrystalline.it Thank you for the Attention Closing remarks 21 For more information please contact: luca.covello@polycrystalline.it