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Pharmaceutical cocrystals

Eleonora Freire, Griselda Polla, Ricardo Baggio
Lamotrigine is a drug used in the treatment of epilepsy and related convulsive diseases. The drug in its free form is rather inadequate for pharmacological use due to poor absorption by the patient, which limits its bioavailability. On the other hand, the lamotrigine molecule is an excellent hydrogen-bonding agent and this has been exploited intensively in the search for better formulations. The formulation presently commercialized (under the brand name Lamictal) is rather complex and includes a number of anions in addition to the active pharmaceutical ingredient (API)...
November 1, 2016: Acta Crystallographica. Section C, Structural Chemistry
Samuel Golob, Miranda Perry, Matteo Lusi, Michele R Chierotti, Iztok Grabnar, Lucia Lassiani, Dario Voinovich, Michael J Zaworotko
Vinpocetine is a poorly water soluble weakly basic drug (pKa = 7.1) used for the treatment of several cerebrovascular and cognitive disorders. Because existing formulations exhibit poor bioavailability and scarce absorption, a dosage form with improved pharmacokinetic properties is highly desirable. Cocrystallization represents a promising approach to generate diverse novel crystal forms and to improve the aqueous solubility and in turn the oral bioavailability. In this article, a novel ionic cocrystal of vinpocetine is described, using boric acid as a coformer, and fully characterized (by means of differential scanning calorimetry, solid-state nuclear magnetic resonance, powder and single-crystal X-ray diffraction, and powder dissolution test)...
October 24, 2016: Journal of Pharmaceutical Sciences
Prabhakar Panzade, Giridhar R Shendarkar
Pharmaceutical cocrystal is an emerging approach to tailor physicochemical and mechanical properties of drug substances. Cocrystals are composed of API and pharmaceutically acceptable coformer. It can be used to address the solubility, dissolution, mechanical properties, stability of drugs. This review discusses introduction to cocrystal, preparation and characterization, what USFDA says on cocrystal and role of Hansen solubility parameter to predict cocrystal. The effect of cocrystal on drug properties, dependence of cocrystal solubility on pH, concept of drug-drug cocrystal and aerosil 200 as novel cocrystal former and impact of cocrystal on drug pharmacokinetic has also been presented in this review along with highly selected examples of cocrystals...
October 18, 2016: Current Drug Delivery
Sunny Bhardwaj, Maya Lipert, Annette Bak
Poor aqueous solubility of a majority of new small molecule chemical entities is a significant challenge in drug discovery since considerably high exposures are often required to enable pharmacokinetic, pharmacology, and toxicology studies. Pharmaceutical cocrystals have received considerable attention in recent years owing to their potential to improve the physicochemical properties and in vivo performance of poorly soluble drugs. However, physical instability in supersaturated solution/suspension formulations is a major concern for their use in preclinical studies...
September 21, 2016: Journal of Pharmaceutical Sciences
Jenniffer I Arenas-García, Dea Herrera-Ruiz, Hugo Morales-Rojas, Herbert Höpfl
The thermal behavior, phase stability, indicative stability and intrinsic dissolution rates of a series of cocrystals and cocrystal hydrates derived from the pharmaceutically active ingredient acetazolamide (ACZ) and 2-aminobenzamide (2ABAM), 2,3-dihydroxybenzoic acid (23DHBA), 2-hydroxybenzamide (2HBAM), 4-hydroxybenzoic acid (4HBA), nicotinamide (NAM) and picolinamide (PAM) as cocrystal formers have been evaluated. Upon heating in an inert atmosphere most of the cocrystals tested demonstrated first the elimination of the crystal former, followed by ACZ degradation...
September 17, 2016: European Journal of Pharmaceutical Sciences
Mingyu Liu, Chao Hong, Guowen Li, Ping Ma, Yan Xie
Myricetin-nicotinamide (MYR-NIC) nanococrystal preparation methods were developed and optimized using both top down and bottom up approaches. The grinding (top down) method successfully achieved nanococrystals, but there were some micrometer range particles and aggregation. The key consideration of the grinding technology was to control the milling time to determine a balance between the particle size and distribution. In contrast, a modified bottom up approach based on a solution method in conjunction with sonochemistry resulted in a uniform MYR-NIC nanococrystal that was confirmed by powder x-ray diffraction, scanning electron microscopy, dynamic light scattering, and differential scanning calorimeter, and the particle dissolution rate and amount were significantly greater than that of MYR-NIC cocrystal...
September 30, 2016: Nanotechnology
Minshan Guo, Ke Wang, Noel Hamill, Keith Lorimer, Mingzhong Li
The development of enabling formulations is a key stage when demonstrating the effectiveness of pharmaceutical cocrystals to maximize the oral bioavailability for poorly water soluble drugs. Inhibition of drug crystallization from a supersaturated cocrystal solution through a fundamental understanding of the nucleation and crystal growth is important. In this study, the influence of the three polymers of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2-pyrrodidone (60%) and vinyl acetate (40%) (PVP-VA) on the flufenamic acid (FFA) crystallization from three different supersaturated solutions of the pure FFA and two cocrystals of FFA-NIC CO and FFA-TP CO has been investigated by measuring nucleation induction times and desupersaturation rates in the presence and absence of seed crystals...
September 6, 2016: Molecular Pharmaceutics
Wilhelm Maximilian Hützler, Ernst Egert, Michael Bolte
The understanding of intermolecular interactions is a key objective of crystal engineering in order to exploit the derived knowledge for the rational design of new molecular solids with tailored physical and chemical properties. The tools and theories of crystal engineering are indispensable for the rational design of (pharmaceutical) cocrystals. The results of cocrystallization experiments of the antithyroid drug 6-propyl-2-thiouracil (PTU) with 2,4-diaminopyrimidine (DAPY), and of 6-methoxymethyl-2-thiouracil (MOMTU) with DAPY and 2,4,6-triaminopyrimidine (TAPY), respectively, are reported...
August 1, 2016: Acta Crystallographica. Section C, Structural Chemistry
Christoph Loschen, Andreas Klamt
PURPOSE: Solvates are mainly undesired by-products during the pharmaceutical development of new drugs. In addition, solvate formation may also distort solubility measurements. The presented study introduces a simple computational approach that allows for the identification of drug solvent pairs which most likely form crystalline solid phases. METHODS: The mixing enthalpy as a measure for drug-solvent complementarity is obtained by computational liquid phase thermodynamics (COSMO-RS theory)...
November 2016: Pharmaceutical Research
Yong Du, Jiadan Xue
Active pharmaceutical ingredients (APIs) can exist in various types of crystalline forms including polymorphs and cocrystals. These multiple crystalline forms of APIs have district physical and physicochemical characteristics. Vibrational spectroscopic techniques used in solid-state pharmaceutical analysis include mid-infrared, Raman and terahertz spectroscopy. In this review, we will focus on the recent vibrational spectroscopic investigation on the polymorphism and cocrystallization of APIs in pharmaceutical fields...
July 26, 2016: Current Pharmaceutical Design
Andrea Erxleben
Understanding the properties, stability and transformations of the solid-state forms of an active pharmaceutical ingredient (API) in the development pipeline is of crucial importance for process-development, formulation development and FDA approval. Investigation of the polymorphism and polymorphic stability is a routine part of the pre-formulation studies. Vibrational spectroscopy allows the real-time in situ monitoring of phase transformations and probes intermolecular interactions between API molecules, between API and polymer in amorphous solid dispersions or between API and coformer in cocrystals or coamorphous systems and thus plays a major role in efforts to gain a predictive understanding of the relative stability of solid-state forms and formulations...
July 26, 2016: Current Pharmaceutical Design
Shan-Yang Lin
Solid-state mechanochemical grinding is important for promoting cocrystal formation, particularly in the design of new solids in the pharmaceutical industry. Pharmaceutical cocrystals are defined as crystalline materials comprising an active pharmaceutical ingredient (API) and one or more appropriate coformers in a definite stoichiometric ratio, formed via non-covalent interactions. Recently, both the US FDA (2013) and the EU EMA (2015) provided a Guidance for Industry and a Reflection Paper, respectively, emphasizing that cocrystals are a new type of substance with potential applications in the pharmaceutical industry...
July 26, 2016: Current Pharmaceutical Design
Saied Md Pratik, Ayan Datta
Formation of salt and/or cocrystal from organic acid-base mixtures has significant consequences in the pharmaceutical industry and its related intellectual property rights (IPR). On the basis of calculations using periodic dispersion corrected DFT (DFT-D2) on formic acid-pyridine adduct, we have demonstrated that an equimolar stoichiometric ratio (1:1) exists as a neutral cocrystal. On the other hand, the nonequimolar stoichiometry (4:1) readily forms an ionic salt. While the former result is in agreement with the ΔpKa rule between the base and the acid, the latter is not...
August 4, 2016: Journal of Physical Chemistry. B
Mingyu Liu, Chao Hong, Yashu Yao, Hongyi Shen, Guang Ji, Guowen Li, Yan Xie
Myricetin shows low oral bioavailability (<10%) in rats due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as those related to anticancer, anti-diabetes, and hepatic protection. To overcome this issue, in this study, pharmaceutical cocrystals were designed to efficiently deliver myricetin by oral administration. A 1:2 stoichiometric cocrystal of myricetin with proline was prepared successfully by solution crystallization based on the ternary phase diagram (TPD) principle, and it is presented as a new sphericity-like crystalline phase characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM)...
October 2016: European Journal of Pharmaceutics and Biopharmaceutics
Masatoshi Karashima, Kouya Kimoto, Katsuhiko Yamamoto, Takashi Kojima, Yukihiro Ikeda
The aim of the present study was to develop a novel solubilization technique consisting of a nano-cocrystal suspension by integrating cocrystal and nanocrystal formulation technologies to maximize solubilization over current solubilizing technologies. Monodisperse carbamazepine-saccharin, indomethacin-saccharin, and furosemide-caffeine nano-cocrystal suspensions, as well as a furosemide-cytosine nano-salt suspension, were successfully prepared with particle sizes of less than 300nm by wet milling with the stabilizers hydroxypropyl methylcellulose and sodium dodecyl sulfate...
October 2016: European Journal of Pharmaceutics and Biopharmaceutics
Ken-Ichi Izutsu, Tatsuo Koide, Noriyuki Takata, Yukihiro Ikeda, Makoto Ono, Motoki Inoue, Toshiro Fukami, Etsuo Yonemochi
Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality...
June 18, 2016: Chemical & Pharmaceutical Bulletin
Shu Li, Tao Yu, Yiwei Tian, Colin P McCoy, David S Jones, Gavin P Andrews
Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder...
September 6, 2016: Molecular Pharmaceutics
S A Ross, D A Lamprou, D Douroumis
Design and synthesis of pharmaceutical cocrystals have received great interest in recent years. Cocrystallization of drug substances offers a tremendous opportunity for the development of new drug products with superior physical and pharmacological properties such as solubility, stability, hydroscopicity, dissolution rates and bioavailability. It is now possible to engineer and develop cocrystals via 'green chemistry' and environmentally friendly approaches such as solid-state synthesis in the absence of organic solvents...
July 7, 2016: Chemical Communications: Chem Comm
Zhengzheng Zhou, Wanying Li, Wei-Jhe Sun, Tongbu Lu, Henry H Y Tong, Changquan Calvin Sun, Ying Zheng
Two new 1:1 cocrystals of resveratrol (RES) with 4-aminobenzamide (RES-4ABZ) and isoniazid (RES-ISN) were synthesized by liquid assisted grinding (LAG) and rapid solvent removal (RSR) methods using ethanol as solvent. Their physiochemical properties were characterized using PXRD, DSC, solid state and solution NMR, FT-IR, and HPLC. Pharmaceutically relevant properties, including tabletability, solubility, intrinsic dissolution rate, and hygroscopicity, were evaluated. Temperature-composition phase diagram for RES-ISN cocrystal system was constructed from DSC data...
July 25, 2016: International Journal of Pharmaceutics
Geetha Bolla, Ashwini Nangia
Pharmaceutical cocrystals belong to a sub-class of cocrystals wherein one of the components is a drug molecule (or an active pharmaceutical ingredient, API) and the second is a benign food or drug grade additive (generally regarded as safe, GRAS). The two components are hydrogen-bonded in a fixed stoichiometric ratio in the crystal lattice. In the past decade, pharmaceutical cocrystals have demonstrated significant promise in their ability to modify the physicochemical and pharmacokinetic properties of drug substances, such as the solubility and dissolution rate, bioavailability, particle morphology and size, tableting and compaction, melting point, physical form, biochemical and hydration stability, and permeability...
June 28, 2016: Chemical Communications: Chem Comm
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