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Childs S.L.,Renovo Research LLC | Kandi P.,Renovo Research LLC | Lingireddy S.R.,Renovo Research LLC | Lingireddy S.R.,Eli Lilly and Company
Molecular Pharmaceutics | Year: 2013

Cocrystals have become an established and adopted approach for creating crystalline solids with improved physical properties, but incorporating cocrystals into enabling pre-clinical formulations suitable for animal dosing has received limited attention. The dominant approach to in vivo evaluation of cocrystals has focused on deliberately excluding additional formulation in favor of "neat" aqueous suspensions of cocrystals or loading neat cocrystal material into capsules. However, this study demonstrates that, in order to take advantage of the improved solubility of a 1:1 danazol:vanillin cocrystal, a suitable formulation was required. The neat aqueous suspension of the danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to the poorly soluble crystal form of danazol dosed under identical conditions, but the formulated aqueous suspension containing 1% vitamin E-TPGS (TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the bioavailability of the cocrystal by over 10 times compared to the poorly soluble danazol polymorph. In vitro powder dissolution data obtained under non-sink biorelevant conditions correlate with in vivo data in rats following 20 mg/kg doses of danazol. In the case of the danazol:vanillin cocrystal, using a combination of cocrystal, solubilizer, and precipitation inhibitor in a designed supersaturating drug delivery system resulted in a dramatic improvement in the bioavailability. When suspensions of neat cocrystal material fail to return the anticipated bioavailability increase, a supersaturating formulation may be able to create the conditions required for the increased cocrystal solubility to be translated into improved in vivo absorption at levels competitive with existing formulation approaches used to overcome solubility limited bioavailability. © 2013 American Chemical Society.


Strukil V.,Ruder Boskovic Institute | Igrc M.D.,Ruder Boskovic Institute | Fabian L.,University of East Anglia | Eckert-Maksic M.,Ruder Boskovic Institute | And 7 more authors.
Green Chemistry | Year: 2012

The mechanochemical click coupling of isothiocyanates and amines has been used as a model reaction to demonstrate that the concept of a solvent-free research laboratory, which eliminates the use of bulk solvents for either chemical synthesis or structural characterization, is applicable to the synthesis of small organic molecules. Whereas the click coupling is achieved in high yields by simple manual grinding of reactants, the use of an electrical, digitally controllable laboratory mill provides a rapid, quantitative and general route to symmetrical and non-symmetrical aromatic or aromatic-aliphatic thioureas. The enhanced efficiency of electrical ball milling techniques, neat grinding or liquid-assisted grinding, over manual mortar-and-pestle synthesis is demonstrated in the synthesis of 49 different thiourea derivatives. Comparison of powder X-ray diffraction data of mechanochemical products with structural information found in the Cambridge Structural Database (CSD), or obtained herein through single crystal X-ray diffraction, indicates that the mechanochemically obtained thiourea derivatives are pure in a chemical sense, but can also demonstrate purity in a supramolecular sense, i.e. in all structurally explored cases the product consisted of a single polymorph. As an extension of our previous work on solvent-free synthesis of coordination polymers, it is now demonstrated that such polymorphic and chemical purity of selected thiourea derivatives, the latter being evidenced through quantitative reaction yields, can enable the direct solvent-free structural characterization of mechanochemical products through powder X-ray diffraction aided by solid-state NMR spectroscopy. © 2012 The Royal Society of Chemistry.


Lipert M.P.,University of Michigan | Roy L.,University of Michigan | Childs S.L.,Renovo Research LLC | Rodriguez-Hornedo N.,University of Michigan
Journal of Pharmaceutical Sciences | Year: 2015

This work examines cocrystal solubility in biorelevant media (FeSSIF, fed-state simulated intestinal fluid), and develops a theoretical framework that allows for the simple and quantitative prediction of cocrystal solubilization from drug solubilization. The solubilities of four hydrophobic drugs and seven cocrystals containing these drugs were measured in FeSSIF and in acetate buffer at pH 5.00. In all cases, the cocrystal solubility (Scocrystal) was higher than the drug solubility (Sdrug) in both buffer and FeSSIF; however, the solubilization ratio of drug, SRdrug = (SFeSSIF/Sbuffer)drug, was not the same as the solubilization ratio of cocrystal, SRcocrystal = (SFeSSIF/Sbuffer)cocrystal, meaning drug and cocrystal were not solubilized to the same extent in FeSSIF. This highlights the potential risk of anticipating cocrystal behavior in biorelevant media based on solubility studies in water. Predictions of SRcocrystal from simple equations based only on SRdrug were in excellent agreement with measured values. For 1:1 cocrystals, the cocrystal solubilization ratio (SR) can be obtained from the square root of the drug SR. For 2:1 cocrystals, SRcocrystal is found from (SRdrug)2/3. The findings in FeSSIF can be generalized to describe cocrystal behavior in other systems involving preferential solubilization of a drug such as surfactants, lipids, and other drug solubilizing media. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.


Alhalaweh A.,Lulea University of Technology | George S.,Lulea University of Technology | Basavoju S.,Lulea University of Technology | Childs S.L.,Renovo Research LLC | And 2 more authors.
CrystEngComm | Year: 2012

The objective of this study was to screen and prepare cocrystals of the poorly soluble drug nitrofurantoin (NTF) with the aim of increasing its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. Manual LAG and reaction crystallization (RC) experiments were carried out to confirm and scale-up the hits. Seven hits were confirmed to be cocrystals. The cocrystals were characterized by PXRD, Raman and IR spectroscopy, thermal analysis (DSC and TGA) and liquid-state NMR or elemental analysis. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1:1 stoichiometric ratio with urea (1), 4-hydroxybenzoic acid (2), nicotinamide (3), citric acid (4), l-proline (5) and vanillic acid (6). In addition, NTF forms a 1:2 cocrystal with vanillin (7). All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming cocrystals have a higher solubility than the NTF hydrate under these conditions. The crystal structures of 1:1 NTF-citric acid (4) and 1:2 NTF-vanillin (7) were solved by single-crystal X-ray diffraction. The crystal structures of these two cocrystals were analyzed in terms of their supramolecular synthons. © 2012 The Royal Society of Chemistry.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2012

This Small Business Innovation Research (SBIR) Phase I project will develop a drug delivery platform for drugs with poor water solubility. Poor water solubility significantly hinders the delivery of some drug compounds into the body, which leads to poor drug performance. Cocrystals are new materials that can improve the water solubility of a poorly water soluble drug compounds. In order to take advantage of the improved cocrystal properties, a suitable drug delivery system is required. The current drug delivery approaches for cocrystals are failing to control the parameters critical to optimizing performance of poorly soluble cocrystallized drugs. By tuning the effective cocrystal solubility using the innovative approaches proposed here, a robust delivery system for highly soluble cocrystals will be developed. The broader/commercial impacts of this research are the potential to create a tunable drug delivery platform that can result in improvements in drug product performance. This technology will also create new product opportunities for existing drug products (e.g. rapid onset of pain relieving drugs), which can provide society with improved medicines. Cocrystal technology has significant advantages over competing technologies including: 1) the physical properties of cocrystals are superior to the physical forms used in competing technologies, and 2) intellectual property protection is stronger, which creates an increased commercial incentive for adopting cocrystal technology.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 150.00K | Year: 2012

This Small Business Innovation Research (SBIR) Phase I project will develop a drug delivery platform for drugs with poor water solubility. Poor water solubility significantly hinders the delivery of some drug compounds into the body, which leads to poor drug performance. Cocrystals are new materials that can improve the water solubility of a poorly water soluble drug compounds. In order to take advantage of the improved cocrystal properties, a suitable drug delivery system is required. The current drug delivery approaches for cocrystals are failing to control the parameters critical to optimizing performance of poorly soluble cocrystallized drugs. By tuning the effective cocrystal solubility using the innovative approaches proposed here, a robust delivery system for highly soluble cocrystals will be developed.

The broader/commercial impacts of this research are the potential to create a tunable drug delivery platform that can result in improvements in drug product performance. This technology will also create new product opportunities for existing drug products (e.g. rapid onset of pain relieving drugs), which can provide society with improved medicines. Cocrystal technology has significant advantages over competing technologies including: 1) the physical properties of cocrystals are superior to the physical forms used in competing technologies, and 2) intellectual property protection is stronger, which creates an increased commercial incentive for adopting cocrystal technology.


PubMed | Renovo Research LLC
Type: Journal Article | Journal: Molecular pharmaceutics | Year: 2013

Cocrystals have become an established and adopted approach for creating crystalline solids with improved physical properties, but incorporating cocrystals into enabling pre-clinical formulations suitable for animal dosing has received limited attention. The dominant approach to in vivo evaluation of cocrystals has focused on deliberately excluding additional formulation in favor of neat aqueous suspensions of cocrystals or loading neat cocrystal material into capsules. However, this study demonstrates that, in order to take advantage of the improved solubility of a 1:1 danazol:vanillin cocrystal, a suitable formulation was required. The neat aqueous suspension of the danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to the poorly soluble crystal form of danazol dosed under identical conditions, but the formulated aqueous suspension containing 1% vitamin E-TPGS (TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the bioavailability of the cocrystal by over 10 times compared to the poorly soluble danazol polymorph. In vitro powder dissolution data obtained under non-sink biorelevant conditions correlate with in vivo data in rats following 20 mg/kg doses of danazol. In the case of the danazol:vanillin cocrystal, using a combination of cocrystal, solubilizer, and precipitation inhibitor in a designed supersaturating drug delivery system resulted in a dramatic improvement in the bioavailability. When suspensions of neat cocrystal material fail to return the anticipated bioavailability increase, a supersaturating formulation may be able to create the conditions required for the increased cocrystal solubility to be translated into improved in vivo absorption at levels competitive with existing formulation approaches used to overcome solubility limited bioavailability.


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Cocrystal Technology The selection of the solid form of an API has a significant effect on product performance. Polymorphs, hydrates, and salts are the commonly available options if a crystalline form is desired ...


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