Center for Pharmaceutical Physics

Saint Charles, NJ, United States

Center for Pharmaceutical Physics

Saint Charles, NJ, United States

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X-ray powder diffraction, differential scanning calorimetry, infrared absorption spectroscopy, and Raman spectroscopy have been used to study the phenomenon of salt formation in four benzenecarboxylic acids (benzoic acid, phenylacetic acid, hydrocinnamic acid, and 4-phenylbutanoic acid), and in the 1:1 stoichiometric products formed by the cocrystallization of a free acid and a sodium salt. Assignments were derived for the observed peaks in both infrared absorption and Raman spectra of the reactants and their products. In all instances, it was observed that the energy of the antisymmetric stretching mode of the carbonyl group of the free benzenecarboxylic acid invariably shifted to higher energies when that acid formed a cocrystal with a sodium salt of another benzenecarboxylic acid. In addition, the symmetric stretching mode of the benzenecarboxylic acid carbonyl group disappeared in the Raman spectrum of its sodium salt and was also absent in the Raman spectrum of the cocrystal product. It was also found that the antisymmetric carboxylate anion stretching mode, the symmetric carboxylate anion stretching mode, the out-of-plane carboxylate deformation mode, and the vibrational modes associated with the phenyl ring and alkane side chains were not useful spectroscopic tools to differentiate cocrystal and sodium salt, as the observed differences of these vibrational modes did not exhibit significantly consistent differences between the various forms. © 2010 American Chemical Society.


The chloride salts formed by benzylamine and α-methylbenzylamine have been characterized using X-ray powder diffraction, differential scanning calorimetry, and infrared absorption spectroscopy. In addition, X-ray powder diffraction and differential scanning calorimetry have been used to establish formation or lack of formation of the 1:1 stoichiometric salt-cocrystal products containing the chloride salts and their respective free bases. For α-methylbenzylamine (which contains a single dissymmetric center), the chiral identities of the free bases and chloride salts were found to play a determining role as to whether a salt-cocrystal product could or could not be formed. It was found that a salt-cocrystal product could only be formed if the salt and free base were of opposite absolute configurations. For those systems where the existence of cocrystals was demonstrated, assignments were derived for the observed peaks in the infrared absorption spectra of the reactants and their products. © 2011 American Chemical Society.


Brittain H.G.,Center for Pharmaceutical Physics
Crystal Growth and Design | Year: 2012

The literature published during 2010 whose subject matter encompasses the cocrystallization of organic compounds having particular interest to pharmaceutical scientists has been summarized in an annual review. The papers cited in this review were drawn from the major physical, crystallographic, and pharmaceutical journals. After a brief introduction, the review is divided into sections that cover articles of general interest, the preparation of cocrystal systems and methodologies for their characterization, and more detailed discussion of cocrystal systems containing pharmaceutically relevant compounds. A brief summary of the state of the art of pharmaceutical cocrystals is also included, which poses an issue that is of great importance to the field. © 2011 American Chemical Society.


Brittain H.G.,Center for Pharmaceutical Physics
Profiles of Drug Substances, Excipients and Related Methodology | Year: 2012

The polymorphic (crystal systems for which a substance can exist in structures defined by different unit cells, and where each of the forms has the same elemental composition) and solvatomorphic (systems where the crystal structures of the substance are defined by different unit cells, but where these unit cells differ in their elemental composition through the inclusion of one or molecules of solvent) landscape of aripiprazole has been critically evaluated in order to learn how many authentic crystal forms have actually been discovered. After a survey of the patent and open literature, it was determined that aripiprazole has been crystallized in nine genuine polymorphic forms and in eight genuine solvatomorphic forms. It was also learned that several other reported "crystal forms" did not consist of a single solid-state phase, and were most likely mixtures of different structures. © 2012 Elsevier Inc.


Brittain H.G.,Center for Pharmaceutical Physics
Profiles of Drug Substances, Excipients and Related Methodology | Year: 2010

The chapter focuses on the literature published primarily during 2007 and 2008 regarding cocrystal systems that have a pharmaceutical interest. The literature cited in the chapter reviews primarily from the major physical, crystallographic, and pharmaceutical journals, and consequently the coverage cannot be represented as being encyclopedic or comprehensive. The particular area of solid-state research has led pharmaceutical scientists into the areas of crystal engineering and assembly of appropriate supramolecular synthons, with particular emphasis on understanding the origins of the molecular self-assembly that takes place in the formation of Cocrystal systems. The chapter also summarizes the works, where drug substances have been obtained as Cocrystal and hence, are of pharmaceutical interest. It was learned that the physical and chemical stability of the formulations containing the carbamazepine-saccharin Cocrystal product were similar to those of carbamazepine in the marketed product, and comparative bioavailability studies demonstrated that the Cocrystal was a viable alternative drug substance to the anhydrous drug form used in the conventional solid dose forms. A great deal of understanding into the formation of Cocrystal has been deduced through studies, in which mixed crystals were prepared by the interaction of carboxylic acids with either nicotinamide or isonicotinamide. In a demonstration of the pharmaceutical advantage that can be realized through the use of a Cocrystal form of a substance, it was shown that the 1:1 Cocrystal of caffeine and methyl gallate exhibited significantly improved powder compaction properties. During the course of study of the salts formed by saccharin with quinine, haloperidol, mirtazapine, pseudoephedrine, lamivudine, risperidone, sertraline, venlafaxine, zolpidem, and amlodipine, a 1:1 Cocrystal of saccharin and piroxicam was detected. © 2010 Elsevier Inc.


Brittain H.G.,Center for Pharmaceutical Physics
Profiles of Drug Substances, Excipients and Related Methodology | Year: 2011

As scientists become more aware of a substantial expansion in the scope of solid-state structural variations that can be obtained through the cocrystallization of several molecules in a single lattice structure, studies of the mixed molecular crystal systems known as cocrystals have mushroomed. Along these lines, workers have researched the assembly of supramolecular synthons and crystal engineering in ever-increasing efforts to produce materials having new and useful properties.For the purposes of this review, cocrystal systems will be regarded as those mixed crystal systems where the individual components exist as solids under ambient conditions. Particularly useful guidance has been provided by Aakeröy, where cocrystal formation from supramolecular synthons is to be considered as forming from discrete neutral molecular species that are solids at ambient temperatures, and where the cocrystal is a structurally homogeneous crystalline material that contains the building blocks in definite stoichiometric amounts. © 2011 Elsevier Inc.


Brittain H.G.,Center for Pharmaceutical Physics
Journal of Pharmaceutical Sciences | Year: 2013

Solid crystalline phases containing two cocrystallized components offer a new development pathway whereby one can potentially improve the physical characteristics (i.e., equilibrium solubility, dissolution rate, solid-state stability, etc.) of a drug substance that exhibits a profile that is less than desirable. In this commentary, the topic of pharmaceutical cocrystals will be briefly explored, and a short exposition of the solubility and dissolution rate advantages that have been realized in various systems will be provided. The Guidance for Industry document recently proposed by United States Food and Drug Administration will be outlined, and its requirements explained. Finally, the subset of pharmaceutical cocrystals that consist of a drug substance and a salt of that substance (termed a salt cocrystal) will be examined to illustrate this additional class of pharmaceutical cocrystals that may offer significant scientific and regulatory advantages. © 2012 Wiley Periodicals, Inc.


Brittain H.G.,Center for Pharmaceutical Physics
Crystal Growth and Design | Year: 2012

The literature published during 2011 whose subject matter encompasses the cocrystallization of organic compounds having particular interest to pharmaceutical scientists has been summarized in an annual review. The papers cited in this review were drawn from the major physical, crystallographic, and pharmaceutical journals. After a brief introduction, the review is divided into sections that cover articles of general interest, the preparation of cocrystal systems and methodologies for their characterization, and more detailed discussion of cocrystal systems containing pharmaceutically relevant compounds. The review ends with a discussion of the draft Guidance for Industry document regarding the regulatory classification of pharmaceutical cocrystals that was issued at the end of 2011 by the Center for Drug Evaluation and Research (CDER) of the United States Food and Drug Administration. © 2012 American Chemical Society.


Brittain H.G.,Center for Pharmaceutical Physics
Journal of Pharmaceutical Sciences | Year: 2011

Research papers and issued patents involving polymorphism (i.e., crystal systems for which a substance can exist in structures characterized by different unit cells, but in which each of the forms has exactly the same elemental composition) and solvatomorphism (i.e., systems in which the crystal structures of the substance are defined by different unit cells, but wherein these unit cells differ in their elemental composition through the inclusion of one or more molecules of solvent) have been summarized in an annual review. The works cited in this review were published during 2009, and were sourced from the major physical, crystallographic, and pharmaceutical journals. The review is divided into sections that cover articles of general interest, computational and theoretical studies, preparative and isolation methods, structural characterization, properties of polymorphic and solvatomorphic systems, studies of phase transformations, effects associated with secondary processing, and US patents issued during 2009. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association.


The salt and stereoselective cocrystal phenomena associated with 2-phenylglycinol and 2-phenylglycine have been studied using X-ray powder diffraction and differential scanning calorimetry. The chiral identities of the free acids and their sodium salts, or the free bases and their chloride salts, were found to play a determining role as to whether a salt-cocrystal product could or could not be formed. In particular, when cocrystallization of an enantiomerically pure basic or zwitterionic substance with its enantiomerically pure acid addition salt was attempted, a salt-cocrystal was only obtained when the absolute configuration of the two reactants is opposite. On the other hand, it has been found that no stereoselectivity in salt-cocrystal formation existed in the cocrystallization of an enantiomerically pure acidic or zwitterionic substance with its enantiomerically pure base addition salt. Copyright © 2012 Wiley Periodicals, Inc.

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