Regulatory Classification of 
Pharmaceutical Co-Crystals 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2018 
Pharmaceutical Quality/CMC 
Revision 1 
 
 
  Regulatory Classification of 
Pharmaceutical Co-Crystals 
Guidance for Industry 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2018 
Pharmaceutical Quality/CMC 
Revision 1 Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DISCUSSION .................................................................................................................... 2 
GLOSSARY .................................................................................................................................. 4  Contains Nonbinding Recommendations 
Regulatory Classification of Pharmaceutical Co-Crystals 
   Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.     
 
 
 
 
I.  INTRODUCTION  
 
This guidance provides applicants planning to submit new drug applications (NDAs) and 
abbreviated new drug applications (ANDAs) with information on the appropriate regulatory 
classification of pharmaceutical co-crystal solid-state forms.2  This guidance also provides 
information about the data that applicants should submit to support the appropriate classification 
of a co-crystal as well as the regulatory implications of the classification. 
 
The recommendations in this guidance apply to materials that the Agency has not previously 
evaluated and determined to be pharmaceutical co-crystals.  The recommendations do not apply 
to materials that the Agency has previously designated as salts, complexes, or other non-co- 
crystalline forms.  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
II.  BACKGROUND 
 
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 
                                                 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research at the Food and Drug Administration. 
2 This guidance finalizes the August 2016 revised draft guidance for industry Regulatory Classification of 
Pharmaceutical Co- Crystals, which classified co-crystals as a drug product intermediate (or as an in-process 
material), and replaces the 2013 guidance of the same name. 
  1  Contains Nonbinding Recommendations 
forms beyond conventional solid-state forms of an API, such as salts and polymorphs.3  Co-
crystals can be tailored to enhance drug product bioavailability and stability and to enhance the 
processability of APIs during drug product manufacture.4  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. 
 
III.  DISCUSSION     
 
Co-crystals are distinguished from salts because unlike salts, the components that co-exist in the 
co-crystal lattice with a defined stoichiometry interact nonionically.  In addition, 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, and 3) multicomponent phases such as solvate and hydrate forms.5  
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.6 
 
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: 
 
Generally speaking, if the API and its coformer have a pKa (pKa (conjugate acid of 
o 
base) - pKa (acid)) > 1, there will be substantial proton transfer resulting in ionization 
and potential formation of a salt as opposed to a co-crystal. On the other hand, if the 
API and its coformer have a pKa (pKa (conjugate acid of base)  - pKa (acid)) < 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. 
 
                                                 
3 For the purposes of this guidance, the term active pharmaceutical ingredient is synonymous with the term drug 
substance (as defined in 21 CFR 314.3). 
4 Schultheiss, N and A Newman, 2009, Pharmaceutical Cocrystals and Their Physicochemical Properties, Crystal 
Growth & Design, 9(6):29502967; Shan, N and MJ Zaworotko, 2008, The Role of Cocrystals in Pharmaceutical 
Science, Drug Discovery Today, 13(910):440446. 
5 See the guidance for industry ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug 
Substances and New Drug Products: Chemical Substances. We update guidances periodically. To make sure you 
have the most recent version of a guidance, check the FDA Drugs guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
6 Note that USP infrared identity test <197> may not be applicable when comparing co-crystals with different 
coformers. 
  2  Contains Nonbinding Recommendations 
If, however, it is determined that the classification of the pharmaceutical solid as a salt 
o 
or co-crystal is not predicated on these relative pKa values, use spectroscopic tools 
and other orthogonal approaches to provide evidence to the contrary.  
 
  Assurance that substantial dissociation of the API from its co-crystal form occurs before 
reaching the site of pharmacological activity.  Given that the interaction of the API with its 
coformer is of similar magnitude to the interaction of the API with solvents in solvates, an 
in vitro evaluation based on dissolution and/or solubility is generally considered sufficient 
to demonstrate that the API dissociates from its coformer before reaching the site of 
pharmacological activity. 
 
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.7  Specifically, it is not regarded as a new API.8  From a 
regulatory perspective, drug products that are designed to contain a new co-crystal are 
considered analogous to a new polymorph of the API.  A co-crystal that is composed of two or 
more APIs (with or without additional inactive coformers) will be treated as a fixed-dose 
combination product and not a new single API. 
 
If you are using a material that the Agency previously considered to be a co-crystal, you may 
continue to do so.  In new applications formatted as common technical documents, provide 
evidence of the previous co-crystal designation in section 3.2.S.1 (Components of the Drug 
Substance).9 
 
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).   
                                                 
7 See the guidance for industry ANDAs: Pharmaceutical Solid Polymorphism. 
8 Different co-crystals of a salt API will be treated as a polymorph of that salt. 
9 For information on common technical documents, see 
http://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/electronicsubmissions/ucm1
53574.htm. 
  3  Contains Nonbinding Recommendations 
GLOSSARY 
 
Co-crystals: Crystalline materials composed of two or more different molecules, one of which 
is the API, in a defined stoichiometric ratio within the same crystal lattice that are associated by 
nonionic and noncovalent bonds. 
 
Coformer:  A component that interacts nonionically with the API in the crystal lattice, that is 
not a solvent (including water), and is typically nonvolatile.  
 
Polymorphs: Different crystalline forms of the same API. This may include solvation or 
hydration products (also known as pseudopolymorphs) and amorphous forms. Per the current 
regulatory scheme, different polymorphic forms are considered the same APIs. (See guidance 
for industry ANDAs: Pharmaceutical Solid Polymorphism.) 
 
Salts: Any 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. Per the current regulatory scheme, different salt forms of the same 
active moiety are considered different APIs. (See 21 CFR 314.108 and 21 CFR 320.1(c).) 
  4