title: Cocrystalline Solids of Telaprevir with Enhanced Oral Absorption.
abstract: A combination of coformer screening and modeling, followed by characterization using calorimetry, structure elucidation, and solubility led to the identification of novel crystalline forms of the hepatitis C protease inhibitor, telaprevir. The lead crystalline form, a cocrystalline solid of telaprevir with 4-aminosalycilic acid, was identified among the list of possible cocrystals via modeling and confirmed by initial screening. It displayed the most significant aqueous solubility improvement over the neat crystalline form. Enhancement of in vivo performance was further demonstrated: a 10-fold increase in bioavailability was achieved for the cocrystal in comparison to the neat nanocrystalline telaprevir and it was found to be not statistically different from the lead amorphous spray-dried formulation.
authors.affiliation: Vertex Pharmaceuticals, Incorporated, Boston, Massachusetts.
authors.forename: Kathy
authors.initials: K
authors.lastname: Stavropoulos
authors.affiliation: (Vertex Pharmaceuticals, Incorporated) Currently at SycnovAte, Inc., Litchfield, New Hampshire.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Johnston
authors.affiliation: Vertex Pharmaceuticals, Incorporated, Boston, Massachusetts.
authors.forename: Yuegang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Vertex Pharmaceuticals, Incorporated, Boston, Massachusetts.
authors.forename: Bhisetti Govinda
authors.initials: BG
authors.lastname: Rao
authors.affiliation: (Vertex Pharmaceuticals, Incorporated) Currently at Gilead Sciences, Incorporated, Foster City, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Hurrey
authors.affiliation: Vertex Pharmaceuticals, Incorporated, Boston, Massachusetts.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hurter
authors.affiliation: (Vertex Pharmaceuticals, Incorporated) Currently at Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Topp
authors.affiliation: Vertex Pharmaceuticals, Incorporated, Boston, Massachusetts.
authors.forename: Irina
authors.initials: I
authors.lastname: Kadiyala
mesh_terms: D010131:Aminosalicylic Acid / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D003890:Desiccation; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D033362:Powder Diffraction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D010131:Aminosalicylic Acid; D000998:Antiviral Agents; D009842:Oligopeptides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir
keywords: anti-viral; cocrystal; coformer; crystal engineering; formulation; solid state; solubility; telaprevir