Pharmaceutical co-crystal compositions
Inventors
ALMARSSON OERN, null • Almarsson, Örn • Bourghol Hickey, Magali • Peterson, Matthew L. • Zaworotko, Michael J. • Moulton, Brian • Rodriguez-Hornedo, Nair
Assignees
University of South Florida • University of Michigan Ann Arbor • University of South Florida St Petersburg • Kenvue Brands LLC
Publication Number
US-7927613-B2
Publication Date
2011-04-19
Expiration Date
2022-09-03
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Abstract
A pharmaceutical composition comprising a co-crystal of an API and a co-crystal former; wherein the API has at least one functional group selected from ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile diazo, organohalide, nitro, s-heterocyclic ring, thiophene, n-heterocyclic ring, pyrrole, o-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, pyridine and the co-crystal former has at least one functional group selected from amine, amide, pyridine, imidazole, indole, pyrrolidine, carbonyl, carboxyl, hydroxyl, phenol, sulfone, sulfonyl, mercapto and methyl thio, such that the API and co-crystal former are capable of co-crystallizing from a solution phase under crystallization conditions.
Core Innovation
The invention provides pharmaceutical co-crystals consisting of an active pharmaceutical ingredient (API) and a co-crystal former, where the constituents are hydrogen-bonded. The API has at least one functional group selected from a comprehensive list (including, but not limited to, ether, alcohol, amine, carboxylic acid, amide, nitrile, and various heterocycles), and the co-crystal former similarly possesses functional groups chosen from a corresponding list (such as amine, amide, carboxyl, phenol, sulfone, mercapto, and others). This co-crystallization may occur from the solid state or solution phase under crystallization conditions.
The patent addresses the problem of improving and modulating the physicochemical properties of APIs, which can exist in various forms (free acid, free base, salt, hydrate, amorphous, or polymorph). Differences in crystalline state can strongly affect an API's solubility, stability, bioavailability, dissolution rate, hygroscopicity, morphology, and shelf-life, resulting in processing and performance challenges—especially for oral dosage forms. As stated in the background, it is desirable to develop new forms of APIs with significantly improved properties for oral formulations and more optimal therapeutic profiles.
By utilizing new co-crystalline forms, the invention enables modulation and often improvement of critical properties such as aqueous solubility, chemical and physical stability, dissolution rate in different media, bioavailability, dose response linearity, hygroscopicity, and crystal morphology. These co-crystals can address limitations associated with poorly soluble or unstable APIs, facilitate processing by altering crystal habit, provide more consistent dose responses, and expand formulation possibilities for both soluble and difficult-to-salt compounds.
Claims Coverage
There are two independent claims in this patent: one to the co-crystal itself and one to pharmaceutical compositions containing the co-crystal. Each claim defines inventive features based on the specific combinations of APIs and co-crystal formers, with the requirement of hydrogen bonding.
Co-crystal of specific API and co-crystal former hydrogen bonded
A co-crystal comprising an API and a co-crystal former selected from the following specific pairs: - carbamazepine and saccharin - carbamazepine and nicotinamide - carbamazepine and trimesic acid - celecoxib and nicotinamide - celecoxib and 18-crown-6 - 5-fluorouracil and urea - acetaminophen and 4,4′-bipyridine - phenytoin and pyridone - aspirin and 4,4′-bipyridine - ibuprofen and 4,4′-bipyridine - flurbiprofen and 4,4′-bipyridine - flurbiprofen and trans-1,2-bis(4-pyridyl) ethylene - carbamazepine and p-phthalaldehyde - carbamazepine and 2,6-pyridinecarboxylic acid - carbamazepine and 5-nitroisophthalic acid - carbamazepine and 1,3,5,7-adamantane tetracarboxylic acid - carbamazepine and benzoquinone wherein the API and co-crystal former are hydrogen bonded to each other.
Pharmaceutical composition containing a co-crystal of specific API and co-crystal former
A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient, or carrier and a co-crystal as defined above—i.e., the co-crystal of an API and a co-crystal former from the enumerated specific pairs (see above), with the API and co-crystal former hydrogen bonded to each other.
The claims cover explicitly defined and hydrogen-bonded co-crystal pairs of APIs and co-crystal formers, as well as pharmaceutical compositions containing these co-crystals together with standard formulation components.
Stated Advantages
Improved aqueous solubility of the API through co-crystal formation.
Improved stability of the API in a co-crystalline form.
Increased dissolution rates in water, simulated gastric fluid, or simulated intestinal fluid.
Enhanced bioavailability, including increased area under the curve (AUC), higher Cmax, and reduced time to Tmax.
Improved processability, such as better crystal morphology and reduced aggregation.
Ability to obtain stable crystalline forms of APIs that are amorphous or difficult to crystallize.
Reduction in hygroscopicity compared to reference forms of the API.
Improved dose response, including more linear or increased dose-response curves.
Suitability for unsaltable or difficult-to-salt APIs.
Reduction in form diversity, including polymorphism and different crystal habits.
Documented Applications
Preparation of pharmaceutical compositions for oral administration in the form of tablets, capsules, powders, suspensions, and elixirs.
Use of co-crystals to improve the solubility, stability, bioavailability, and dose response of APIs in oral dosage forms.
Incorporation of co-crystals into controlled- or delayed-release formulations, including osmotic drug delivery systems (OROS® systems) and other controlled-release technologies.
Crystallization of amorphous APIs or those difficult to salt for pharmaceutical use.
Reduction of hygroscopicity and improvement of shelf-life in API formulations.
Screening and selection of suitable co-crystal formers for new API formulations using high-throughput crystallization techniques.
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