Regulatory Considerations on Pharmaceutical Solids: Polymorphs/Salts and Co-Crystals

Transcription

1 Regulatory Considerations on Pharmaceutical Solids: Polymorphs/Salts and Co-Crystals ndre S. Raw, Ph.D Director- Division of Chemistry I FD-CDR-Office of eneric Drugs andre.raw@fda.hhs.gov *Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of the FD 1

2 Overview 1. Regulatory Scheme on Polymorphs/Salts 2. Regulatory Scheme on Co-Crystals??? 2

3 Part I Regulatory Scheme on Polymorphs 3

4 Solid-State Polymorphism Different crystalline forms of the same drug substance (ICH Q6) Crystalline forms Solvates (Hydrates) morphous forms 4

5 Drug Product Bioavailability/Bioequivalence Solubility/Dissolution Pharmaceutical Solid Polymorphism Mechanical Properties/ Hygroscopicity Chemical Reactivity Processability / Manufacturability Stability 5

6 Polymorphism and the ffect on Bioavailability Form I Conc Time Intestinal Membrane Dissolution/Solubility Limited Oral bsorption (e.g. chloramphenicol palmitate) Form II Intestinal Membrane Solubility: Form II > Form I Conc Time astric mptying or Permeation Limited Oral bsorption (e.g. ranitidine HCl) 6

7 Polymorphism and the ffect on Stability Trihydrate: Degradation: 0.5% (Samples from the Market) morphous: Degradation: 4.5% (Samples from the Market) Citizen Petition: Docket No P-0315 Formulation I torvastatin Calcium Trihydrate/morphous Formulation II Basic xcipients: lter ph microenvironment Butylated Hydroxy nisole (nti-oxidant) Trihydrate: Degradation 1.6% (40 o C/75% RH, 3 Month) morphous Degradation 1.7% (40 o C/75% RH, 3 Month) S. Wankhede, J. Chem Pharm Res. 2(5) (2010)

8 Polymorphism and the ffect on Manufacturability Paracetamol Form I Paracetamol Form I I Direct Compression Wet ranulation Paracetamol Form I Paracetamol Form I I. Joiris, Pharm. Res. 15 (1998)

9 QbD Paradigm: Polymorphs From ICH Q8: The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g. solid state properties), should be identified and discussed. xpectation that sponsors justify in pharmaceutical development the selection and control of the polymorphic form (as applicable) to achieve drug product performance characteristics, stability and ensure manufacturability 9

10 Regulatory Considerations: Can One Consider Polymorphs to be the Same ctive? S C H 3 N O 2 N H C N Form I Form II 8 6 Conc Materials Science J. m. Chem. Soc. 122 (2000) Time Drug Product Safety/ffectiveness 10

11 Regulation: Solid State Forms NDs May Use Different Polymorphic Forms To Design a Drug Product with quivalent Performance Characteristics to the RLD Preamble 1992 Final Rule: FD specifically rejected requirement that PI in the eneric and RLD product exhibit the same physical characteristics and solid state forms of the drug have not been altered. Regulatory Scheme for NDs: Polymorphic Forms of PI are the Same 11

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13 Part IB Regulatory Scheme on Salts 13

14 Salts ny of numerous compounds that result from replacement of part or all of the acid hydrogen of an acid by a metal or a radical acting like a metal: an ionic or electrovalent crystalline compound.. 14

15 Salts May or May Not nhance Performance Characteristics Differing Bioavailabilities for LY Salts (Mesylate/Chloride) Similar Bioavailabilities for Quinine Salts (thyl Carbonate/Chloride/Sulfate). ngel, Int. J Pharmaceutics 198 (2000) p Jamaludin, Br J. Clin. Pharmac 25 (1988) p

16 FD Regulatory Scheme 21 CFR 320.1(c), Food and Drugs, Definitions: Pharmaceutical equivalent means drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety ; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency. Same ctive Moiety Phosphate Different ctive Ingredients Sulfate FD Regulatory Scheme: Pharmaceutical lternatives No Possibility for Therapeutic quivalence for Different Salts 16

17 M Regulatory Scheme rticle 10.2.b of Directive 2001/83/C: The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant M Regulatory Scheme: More Flexible and Possible Therapeutic quivalence for Different Salts with Supporting Data 17

18 Part II Regulatory Scheme on Co-Crystals??? 18

19 What are Co-Crystals Multiple Component Crystal in Which ll Components are Solid Under mbient Conditions (M.J. Zawarotki) Molecular Complex that Contains Two or More Different Molecules in the Same Crystal Lattice (.P. Stahly) Definitions enerally Distinguish Co-crystals From Salts 19

20 20 Co-Crystals C- + C- C- C- C- C- C- C C- + C- C- C- C- C- C- C Salts Co-crystals Polymorphs

21 PI Potential Utility of Co-Crystals PI No Ionizable roups Probable Molecular Recognition : Patterns (e.g. H-bonding Rules) with uest Compound Co-Crystal Solid State ngineering Salt Form: nhanced Pharmaceutical Properties Improved PI Cocrystal Solid State Properties 21

22 Crystal Solid State ngineering Based Upon H-Bonding Motifs Piroxicam mide H-Bonding Network (III) Piroxicam-Hydroxybenzoic cid Co-Crystal Carboxylic cid-mide H-Bonding (IV) P. Vishweshwar, J. Pharmaceutical Science, 95(3) 2006, p

23 Co-Crystals May nhance Drug Product Properties: Bioavailability I : lutaric acid Cocrystal I I Candidate Drug I (Low Solubility 0.1 µg/ml pka of conjugate acid (-0.5)) D. McNamara, Pharmaceutical Research 23 (2006) p

24 Co-Crystals May nhance Drug Product Properties: Processability Paracetamol Form I (Stable Form) Crystal Lattice Compact Currugated Layers Difficult to Compress S. Karki, dvanced Materials, 21 (2000) p

25 Optimize Drug Product Stability nhance Drug Product Bioavailability Co-crystals: Opportunities Crystal ngineering nhance Manufacturing fficiency 25

26 Where Do Co-Crystals Fit in Our Regulatory Scheme? C- C- C- C C- C- C- C- + + Salts + Same ctive Moiety Different PI Co-crystals?? Where Do Co-Crystals Fit? Is a New Regulatory Class of Solids Needed? Polymorphs Same PI 26

27 nhance Pharmaceutical Characteristics in Drug Product Design Regulatory Scheme For Co-Crystals Make Regulatory and Labeling Claims that the Co-Crystal Constitutes a Novel ctive Ingredient Regulatory Strategy to Block Competition 27

28 nalysis: Formulating Regulatory Policy 21 CFR 210.3(b)(4): drug product is a finished dosage form (e.g., tablet; capsule; or solution that contains an active pharmaceutical ingredient generally, but not necessarily, in association with inactive ingredients (excipients)). 28

29 29 Physical ssociation (PI xcipient) PI with Lactose Dry Blend ssociation of ctive Ingredient with xcipients in Drug Product Molecular ssociation (PI xcipient) PI-Co-Crystals Distinguishable by Having a Crystal Lattice PI Inclusion Complexes (e.g. Cyclodextrin) PI Molecular Dispersions

30 Co-Crystal Regulatory Scheme C- C- C- C C- C- C- C Co-crystals Salts No Need to Create New Category Of Solid-State Form Polymorphs Fits Nicely Within Our Framework s an ctive Ingredient Drug Product Intermediate 30

31 Co-Crystal Regulatory Scheme: Corollary n PI excipient co-crystal that meets these conditions is a pharmaceutical co-crystal and has a regulatory classification of a drug product intermediate. Specifically, it is not regarded as a new PI. Drug products that contain PI excipient co-crystals are not considered to contain new PI, but rather a specifically designed component called a co-crystal drug product intermediate. 31

32 Considerations in Review of CoCrystals 1. Determine whether, in the crystalline solid, the component PI with the excipient compounds in the co-crystal exist in their neutral states and interact via nonionic interactions, as opposed to an ionic interaction, which would classify this crystalline solid as a salt form. a. enerally speaking, if PI and its excipient(s) have a ΔpKa (pka (base) - pka (acid)) < 0, there will be negligible proton transfer and the molecular complex will be a co-crystal. b. If the ΔpKa > 3, there will be complete proton transfer resulting in complete ionization and formation of a salt as opposed to a co-crystal. c. In instances where the ΔpKa > 0 and ΔpKa < 3, the extent of proton transfer and ionization is generally not predictable. Rely on Spectroscopic tools to resolve this. 2. For pharmacological activity, ensure that the PI dissociates from its excipient prior to reaching the site of action. 32

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34 Common Themes from Docket 34

35 1. Co-crystals be new alternative PIs: Some reasons cited - Co-crystal is typically fully characterized for solid-state properties similar to an PI - Drug substance release and stability testing is performed on the co-crystal - Co-crystals are manufactured at PI facilities (not drug product facilities). - PI is not isolated during synthesis, but rather isolated as a co-crystal. - Drug product manufacturing facilities do not typically generate co-crystal intermediates The type and extent of characterization and release testing performed on the active pharmaceutical ingredient, the co-crystal intermediate, or both should be sufficient to ensure the identity, strength, quality, and purity of the active ingredient, critical process intermediates, and drug product. Regardless of whether the co-crystal is manufactured in an PI manufacturing facility or in one typically used to manufacture drug product (dosage form), the co-crystal should be manufactured in a facility that operates in accordance with current good manufacturing practice (CMP). 35

36 2. Classify co-crystals as salts: Conceptually no different than salts. The approach to distinguishing co-crystals from salts is flawed - Solution state pkas are not representative of the pkas in a co-crystal lattice. - Determining the location of the proton by spectroscopic tools is difficult, if not impossible. - Distinguishing between a salt and co-crystal would place undue burden to the industry. - This would also result in endless debate among industry/reviewers on classification enerally speaking, if the PI and its excipient(s) have a ΔpKa (pka (base) - pka (acid)) > 1, there will be substantial proton transfer resulting in ionization and formation of a salt as opposed to a co-crystal. On the other hand, if the PI and its excipient(s) have a ΔpKa (pka (base) - pka (acid)) < 1, there will be less than substantial proton transfer. If this criterion is met, the active ingredient-excipient complex should be classified as a co-crystal. If, however, you believe that the classification of the pharmaceutical solid as a salt or co-crystal is not predicated on these relative pka values, then spectroscopic tools using various orthogonal approaches should be used to prove otherwise. 36

37 3. For pharmacological activity of co-crystals, what are the data requirement expectations to ensure the PI dissociates from its excipient prior to reaching the site of action? nalogous approaches can be used to demonstrate that for an active moiety s given salt form, the active moiety dissociates from its corresponding counterion prior to reaching the site of pharmacological action. 4. Classify the co-crystals as salts but take the broader approach of changing the FD regulations in relation to salts to be similar to the M approach. 37

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39 cknowledgements Lawrence Yu Keith Webber Richard Lostritto (ONDQ) OD and ONDQ Directors 39