polymorphs and co-crystals

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राष्ट्रीय औषधीय शिक्षा एवं अनुसंधान संस्थान (नाईपर), हैदराबाद
Presented by:
Mr. Parimal Hadge
PE/2019/311
Department of Pharmaceutics
NIPER-HYDERABAD
Latest Regulatory Guidelines – Polymorphs and Cocrystals

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Contents
Introduction
Structural aspects of polymorph
Properties of polymorphs
General principles of pharmaceutical solid polymorphism
How Guidelines came into picture??
Case study: The Ritonavir Story
Guidance foe Industry
Co-crystals
References

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Polymorphs
http://www.fda.gov/cder/guidance/index.htm
Polymorphic forms in the context of this guidance refer to crystalline and amorphous forms as well as solvate and
hydrate forms, which are described below.
 Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.
 Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable crystal
lattice.
 Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent.9 If the
incorporated solvent is water, the solvate is commonly known as a hydrate.
Introduction
Different crystalline forms of the same drug substance
(ICH Q6A)
• Crystalline forms
• Solvates (Hydrates)
• Amorphous forms

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Structural aspects of polymorph
• Configurational polymorph occurs
with molecules that have a relatively
rigid conformation. Such
polymorphs have different 3D
structures.
• E.g Carbamazepine
Configurational
polymorph
• Conformational polymorph occurs
with drug molecules that have
flexible structures and the
molecule can take various
conformations.
• E.g Ritonavir
Conformational
polymorph

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Properties of polymorphs
Packing properties
Thermodynamic
properties
Spectroscopic
properties
Kinetic
properties
Surface
properties
Mechanical
properties

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GENERAL PRINCIPLES OF PHARMACEUTICAL SOLID
POLYMORPHISM
chemical and physical
properties, including melting
point, chemical reactivity,
apparent solubility,
Thus, polymorphism can
affect the quality, safety,
and efficacy of the drug
product.
These properties can have a direct
effect on the ability to process
and/or manufacture the drug
substance and the drug product, as
well as on drug product stability,
dissolution, and bioavailability.
A. Importance of Pharmaceutical Solid Polymorphism
dissolution rate, optical
and mechanical
properties, vapor
pressure, and
http://www.fda.gov/cder/guidance/index.htm

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B. Characterization of Polymorphs
Optical
microscopy
Scanning
electron
microscope
Hot stage
microscopy
Single crystal
X-ray
Diffraction
Powder X-ray
Diffraction
Differential
thermal analysis
FTIR
Solid state
NMR
spectroscopy

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C. Influence of Polymorphism On Drug Substance And Drug Product
1. Influence on Solubility, Dissolution, and Bioavailability (BA) and Bioequivalence (BE)
 significant influence on the apparent solubility of the drug substance
 can have different aqueous solubilities and dissolution rates
 When there are differences in the apparent solubilities of the various polymorphic forms, FDA recommend that
focus on the potential effect such differences can have on drug product bioavailability (BA) and bioequivalence
(BE)
 Whether drug product BA/BE can be affected by the differences in apparent solubilities of the various
polymorphic forms depends on the various physiological factors that govern the rate and extent of drug
absorption including gastrointestinal motility, drug dissolution, and intestinal permeability
 In this context, the Biopharmaceutics Classification System (BCS),provides a useful scientific framework for
regulatory decisions regarding drug substance polymorphism.
http://www.fda.gov/cder/guidance/index.htm

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2. Influence on Manufacturing of the Drug Product
 Drug substance polymorphic forms can also exhibit different physical and mechanical properties, including
hygroscopicity, particle shape, density, flowability, and compactibility, which in turn may affect processing of the
drug substance and/or manufacturing of the drug product.
 Since an ANDA applicant should demonstrate that the generic drug product can be manufactured reliably using a
validated process, we recommend that you pay close attention to polymorphism as it relates to pharmaceutical
processing
 The effect of polymorphism on pharmaceutical processing also depends on the formulation and the
manufacturing process
 Polymorphic forms of the drug substance can undergo phase conversion when exposed to a range of
manufacturing processes, such as drying, milling, micronization, wet granulation, spraydrying, and compaction
 Exposure to environmental conditions such as humidity and temperature can also induce polymorph conversion
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

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3. Influence on Stability
 Polymorphs can have different physical and chemical (reactivity) properties.
 The most thermodynamically stable polymorphic form of a drug substance is often chosen during development
based on the minimal potential for conversion to another polymorphic form and on its greater chemical stability
 However, a metastable form can be chosen for various reasons, including bioavailability enhancement .
 Since an ANDA applicant must demonstrate that the generic drug product exhibits adequate stability, FDA
recommend that you focus on the potential effect that a polymorphic form can have on drug product stability

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How Guidelines came into picture??
The Ritonavir Story………….

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 Ritonavir, the active ingredient in Norvir Capsules
(Abbott), was identified as the key component in various
protease inhibitor cocktails (combination therapies) used
for the successful treatment of HIV infections
 By that time, 240 lots of the Norvir Capsules had been
successfully manufactured.
 However, in the summer of 1998, a sudden change in
physical properties of ritonavir brought production to a
halt and eventually led to an interruption of the supply of
Norvir capsules to the millions of HIV patients who relied
on the product for its therapeutic effects.
 crystal form of ritonavir had unexpectedly changed.
 resulted in a solubility change for the drug, which in turn
resulted in a bioavailability change and affected the
therapeutic effect of the drug.
 The Norvir product was withdrawn from the market.
 An intensive research effort was undertaken to understand
and solve the problem. A new capsule formulation was
eventually introduced that overcame the physical problems.
 After implementing the new formulation, Norvir Capsules
were returned to the marketplace

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 This guidance is intended to assist applicants with the
submission of ANDAs when a drug substance exists in
polymorphic forms. Specifically, this guidance
provides:
 FDA recommendations on assessing sameness when
the drug substance exists in polymorphic forms.
 Decision trees that provide recommendations on
monitoring and controlling polymorphs in drug
substances and/or drug products.
Guidance foe Industry

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 CONSIDERATIONS FOR POLYMORPHISM IN
ANDAs:
They provides ANDA applicants with a suggested process
for evaluating the importance of and approaches to setting
specifications for polymorphic forms in solid oral drug
products and oral suspensions. Although the conceptual
framework adopted by these decision trees is based
primarily on the potential for polymorphic forms to affect
drug product BA/BE.
The following sections describe each of the decision trees:
• Investigating the Importance of Setting Specifications for
Polymorphs
• Setting Specifications for Polymorphs in Drug Substances
• Investigating the Importance of Setting Specifications for
Polymorphs in Drug Products

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Setting Specifications for Polymorphs in Drug Substances
Decision Tree 2 provides an approach for setting
specifications for polymorphs in the drug substance when at
least one form is known to have low solubility based on the
BCS. If relevant and adequate specifications for polymorphs
are included in the USP, ANDA applicants may adopt these
specifications for the drug substance polymorphic form.
Otherwise, we recommend that a new specification for the
drug substance polymorphic form be established.

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Investigating the Importance of Setting Specifications for
Polymorphs in Drug Products
Decision Tree 3 provides an approach when considering
whether to set specifications for polymorphs in the drug
product. Generally, specifications for polymorphs in drug
products are not necessary if the most thermodynamically
stable polymorphic form is used or if the same form is used in
an approved product of the same dosage form. However, since
manufacturing processes can affect the polymorphic form, we
recommend that you use caution if a metastable form is used.

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 *In general, there may not be a concern if the most thermodynamically stable polymorphic form is used or
the same form is used in a previously approved product of the same dosage form.
 **Drug product performance testing (e.g., dissolution testing) can generally provide adequate control of
polymorph ratio changes for poorly soluble drugs, which may influence drug product BA/BE. Only in rare
cases would polymorphic form characterization in the drug product be recommended.

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Co-crystals
 Co-crystals are crystalline materials composed of two or more different molecules, typically active
pharmaceutical ingredient (API) and co-crystal formers (“coformers”), in the same crystal lattice.
 Pharmaceutical co-crystals have provided opportunities for engineering solid-state forms beyond conventional
solid-state forms of an API, such as salts and polymorphs.
 Cocrystals can be tailored to enhance drug product bioavailability and stability and to enhance the
processability of APIs during drug product manufacture.
 Another advantage of co-crystals is that they generate a diverse array of solid-state forms for APIs that lack
ionizable functional groups, which is a prerequisite for salt formation.
Introduction

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 Co-crystals differ from polymorphs, which are defined as including:
1) single-component crystalline forms that have different arrangements or conformations of the molecules in the
crystal lattice
2) amorphous forms
3) multicomponent phases such as solvate and hydrate forms
 Instead, co-crystals are more similar to solvates, in that both contain more than one component in the lattice.
 From a physical chemistry and regulatory perspective, co-crystals can be viewed as a special case of solvates
and hydrates, wherein the second component, the coformer, is not a solvent (including water), and is typically
nonvolatile.

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General Definition
“crystalline material comprised of API & one or more
conformers in stoichiometric ratio (1:1, 1:2, 1:3 etc),
which are solid at room temperature”
USFDA (2013
) Definition
“solids which are crystalline materials composed of 2 or
more molecules in same crystal lattice.”
“Indo-US bilateral meeting on Evolving
role of Solid State Chemistry in
Pharmaceutical Science”
“Cocrystals are solids that are crystalline,- single
phase materials composed of 2 or more different
molecular and/or ionic compounds in
stoichiometric ratio which are neither solvates nor
simple salts.”
WHAT IS PHARMCEUTICAL COCRYSTAL??
3 Definitions

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COMPOSITION OF COCRYSTALS
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 COFORMER
 EXCIPIENT
 SOLVENT
 API
Coformers are very important components for
designing and screening of cocrystals.
 They participate in intermolecular interactions
while cocrystallization.
 They become part of cocrystal structure.
 Solubility of cocrystal depends on solubility of
coformers. Selection of coformers is done by
various knowledge based and experimental
methods.
 Commonly used coformers:- Nicotinamide,
Ascorbic acid, Saccharin, Urea, Citric acid,
Glycine etc.
 EXCIPIENTS- Excipients are the other
formulation additives usually added in
oral dosage form. They are chemically
inert & do not become part of crystal
structure.
Examples:- Fillers, Lubricating agents,
Flavors, Colorants, etc.
 SOLVENTS -Solvent mixtures can be
used to thermodynamically suppress
solvate formation as competiting reaction
in solution-based cocrystallization
techniques. Cocrystal formation depends
on selection of solvent.
Examples:- Methanol, ethanol, etc.
Pharmaceutics 2018, 10, 18

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For NDAs and ANDAs containing or claiming to contain a co-crystal form, applicants should submit appropriate data
that support the following:
 Provide evidence to demonstrate that both the API and coformers are present in the unit cell.
 If both API and coformer have ionizable functional groups, a conclusion that the component API and coformer co-
exist in the co-crystal which interact nonionically. Consider the following to guide your decision:
 if the API and its coformer have a ΔpKa > 1, there will be substantial proton transfer resulting in ionization
and potential formation of a salt as opposed to a co-crystal.
 if the API and its coformer have a ΔpKa < 1, there will be less than substantial proton transfer. If this
criterion is met, the API coformer entity should be classified as a co-crystal.
 if these relative pKa values does not classify the product, then use spectroscopic tools and other orthogonal
approaches to provide evidence to the contrary.
 An in vitro evaluation based on dissolution and/or solubility: generally considered sufficient to demonstrate that
the API dissociates from its coformer before reaching the site of pharmacological activity.

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 A co-crystal with a pharmaceutically acceptable coformer that meets the above conditions can be considered to be
a pharmaceutical co-crystal and has a regulatory classification similar to that of a polymorph of the API.
 The type and extent of characterization and release testing performed on the co-crystal should be sufficient to
ensure the identity, strength, quality, and purity of the API(s).

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 Cocrystallisation is a viable alternative to salt formation as well as a
versatile tool that can be used to achieve more appropriate solid state
properties. From a scientific point of view, solvates including hydrates
can be considered as a subgroup of cocrystals; nevertheless the
regulatory context may sometimes differ.
 Cocrystals and salts share many conceptual similarities and therefore also
similar principles for documentation should be applied.
 In case of a complex co-former additional documentation may be
required; a scientific advice procedure is recommended.
 The European Medicines Agency (EMA) defines cocrystals as a variant
of solid forms of APIs, associating them with salts, polymorphs,
hydrates and solvates.
 In 2015, the EMA released a document specifically related to the use of
cocrystals in pharmaceutical research, in addition to the one released in
2014
http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2015/07/WC500189927.pd

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 Cocrystals, hydrates and solvates are held together by weak interactions that are in most cases broken upon
dissolution. This is the same situation as with salts.
 Hence, with respect to oral administration, dissolution of such different forms of a drug substance in the
stomach or the intestinal canal will lead to the release of the same substance, independent on the form that
was taken in. The validity of this assumption is verified by the demonstration of bioequivalence.
 Cocrystals, hydrates and solvates will therefore be considered eligible for generic applications in the same
way as salts are unless they differ with respect to safety and/or efficacy
Cocrystals and abridged applications
Cocrystals and New Active Substance (NAS) status
 Since cocrystals, hydrates and solvates are held together by weak interactions that are in most cases broken upon
dissolution, when such a form, already authorised as a medicinal product in the EU, is administered orally it will
expose a patient to the same therapeutic moiety.
 Just as for salts, they will therefore not be considered as NASs in themselves unless they are demonstrated to be
different with respect to efficacy and/or safety.
http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2015/07/WC500189927.pd

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References:
 European Medicines Agency. Reflection Paper on the Use of Cocrystals of Active Substances in
Medicinal Products. May 2015. Available online:
http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2015/07/WC500189927.pdf (accessed on 2 November 2017).
 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
 Polymorphism—A Critical Consideration in Pharmaceutical Development, Manufacturing, and Stability
 Karagianni, A.; Malamatari, M.; Kachrimanis, K. Pharmaceutical Cocrystals: New Solid Phase Modification
Approaches for the Formulation of APIs. Pharmaceutics 2018, 10, 18.
https://doi.org/10.3390/pharmaceutics10010018

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• In last few years many drugs have been discovered, among them 60- 70% compounds are related to BCS
class II ( high permeability & low solubility).
• This poorly soluble drugs have limited absorption and low bioavailability.
• Poor solubility is most common hindrance in drug development. Hence enhancement of solubility is
major challenge for pharmaceutical researchers.
APPROACHES TO ENHANCE SOLUBILITY
1.Amorphous form.
2. Salt formation.
3. Polymorphs.
4. Nanoparticles.
5. Cocrystals.
6. Solvates.
7. Size reduction.

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Each technique has its own merits and demerits.
• Amongst all this ‘Cocrystals’ approach is unique as it does not affect pharmacological properties of drug,.
• ‘Cocrystals’ can also be used as an alternative approach based on crystal engineering to enhance specific
physicochemical and biopharmaceutical properties of API , when approaches to salt or polymorph formation do not
meet expected targets.

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 POLYMORPHISM AND SAMENESS IN ANDAs:
1. 505(j): For consideration and approval if the generic drug product is the "same as" the RLD
2. Section 505(j)(2): Must contain information to show that the active ingredient in the generic drug product is the "same
as" that of the RLD
3. 505(j)(4): FDA must approve an ANDA unless the agency finds, among other things, that the ANDA contains
insufficient information to show that the active ingredient is the same as that in the RLD
4. 21 CFR 314.92(a)(1): The drug substance in a generic drug product is considered to be the same as the drug substance
in the RLD if it meets the same standards for identity
5. FDA, 1992 final rule: FDA specifically rejected a proposal that would have required an ANDA applicant to show that
the active ingredient in its generic drug product and the active ingredient in the RLD "exhibit the same physical and
chemical characteristics, that no additional residues or impurities can result from the different manufacture or
synthesis process and that the stereochemistry characteristics and solid state forms of the drug have not been altered
Examples: FDA has approved a number of ANDAs in which drug substance of drug product having:
• different polymorphic form: warfarin sodium, famotidine, and ranitidine
• differed in solvate or hydrate forms: terazosin hydrochloride, ampicillin, and cefadroxil