Publications by authors named "Matthew L Peterson"

25 Publications

  • Page 1 of 1

Development of a quantitative method to evaluate the printability of filaments for fused deposition modeling 3D printing.

Int J Pharm 2020 Oct 12;588:119760. Epub 2020 Aug 12.

Pharmaceutical Development, Biogen, Cambridge, MA, USA. Electronic address:

Lack of a conventional quantitative characterization method for filament printability has been recognized as a critical barrier to fused deposition modeling (FDM) 3D printing application. In this study, a small molecule drug, indomethacin, was utilized as a model compound. Polymers with various solubility were mixed with model drug and extruded into filaments using hot melt extrusion method. Thirty-two filaments with or without indomethacin were evaluated by texture analyzer to study the correlation between mechanical properties and the printability. Three different texture analysis methods were utilized and compared, and a parameter "toughness" calculated by stiffness test was identified to quantitatively describe the printability of filaments in the FDM 3D printer. The toughness threshold value of printable filament was defined as a process window of certain FDM printing. This study provides a quantitative way to evaluate and predict filament printability, and it has great potential to be applied to FDM filament development and quality control in the pharmaceutical industry.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119760DOI Listing
October 2020

Impact of Shear History on Powder Flow Characterization Using a Ring Shear Tester.

J Pharm Sci 2019 Jan 9;108(1):750-754. Epub 2018 Aug 9.

Biogen, Technical Development, Cambridge, Massachusetts 02142.

In this study, we have investigated the impact of repeated shear displacement on powder flow properties. We show that when multiple yield loci are obtained using the same bulk solid specimen by stepping through different stress levels (i.e., stress walk [SW]), the shear deformation of the powder in a rotational shear cell, that is, Schulze Ring Shear Tester, is maximized, reducing the powder shear strength. This approach is material and time sparing; however, it imprecisely predicts better powder flowability. The magnitude of the change in the unconfined yield strength, σ, due to this prolonged shear displacement appears to be material-dependent, being less impactful for free-flowing powders. Using the SW and the individual yield loci-generated flow properties, we have demonstrated that in hopper design, the shear displacement effect impacts the computed critical arching diameter more than the critical mass flow angle. This knowledge of powder flow properties highlights limitations associated with the SW. An exponential function was found to describe the relationship between the change in σ at the highest major principal stress and the density weighted flowability, ff, with an R of 0.98. Such a model could be a valuable tool for correcting shear strength results obtained from SW, saving time, and material.
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http://dx.doi.org/10.1016/j.xphs.2018.07.003DOI Listing
January 2019

Structure Determination and Characterization of a Family of Primary Alcohol Solvates.

J Pharm Sci 2018 06 5;107(6):1489-1497. Epub 2018 Feb 5.

Pharmaceutical Sciences, Engineering & Technology, Biogen, Cambridge, Massachusetts 02142.

We report the preparation and structural characterization of a family of primary alcohol solvates of a small-molecule hydrochloride salt. The structures of the solvates are probed by powder and single crystal X-ray diffraction, and the compounds were additionally characterized by polarized light microscopy, thermogravimetric analysis, and dynamic scanning calorimetry. A comparison of the lattices of each compound is also provided. The results demonstrate the existence of a common solvating channel and highlight the importance of understanding the form landscape early in the development process.
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http://dx.doi.org/10.1016/j.xphs.2018.01.020DOI Listing
June 2018

Low colonic absorption drugs: risks and opportunities in the development of oral extended release products.

Expert Opin Drug Deliv 2018 02 14;15(2):197-211. Epub 2017 Oct 14.

a Pharmaceutical Development , Biogen Inc , Cambridge , MA , USA.

Introduction: Currently numerous drugs have been observed with lower colonic absorption than small intestine absorption, which can significantly impact in vivo performance of their oral extended release (ER) products.

Areas Covered: We reviewed over 300 publications, patents, book chapters, and commercial reports of drug products from regulatory agencies for low colonic absorption (LCA) drugs and critical findings are discussed. The focuses of this article are (1) current findings on the causes of low colonic absorption to support early assessment of LCA candidates, and (2) current knowledge on successful ER strategies and technical platforms used for LCA drugs in commercial drug products to facilitate oral ER product development.

Expert Opinion: Colonic drug absorption is one of the critical considerations in successful development of oral ER products. The root causes of low colonic absorption in many LCA drugs are still unclear. It is recommended to evaluate colonic drug absorption of drug candidate at early stage of oral ER product development. After evaluation, the selection of a formulation platform to develop an oral ER product needs to be carefully considered for LCA drugs. Based on the current commercial oral ER formulation platforms for LCA drugs, compounds are first divided into five types (I-V) and different ER formulation approaches with higher success rate are recommended for each type.
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http://dx.doi.org/10.1080/17425247.2018.1389889DOI Listing
February 2018

Conformational isomerism in solid state of AMG 853--structure studies using solid-state nuclear magnetic resonance and X-ray diffraction.

J Pharm Sci 2015 Jul 24;104(7):2161-8. Epub 2015 Apr 24.

Department of Physics and Astronomy, State University of New York, Stony Brook, New York, 11794-3800.

Investigation of an additional resonance peak in the (19) F solid-state nuclear magnetic resonance (NMR) spectrum of AMG 853, a dual antagonist of DP and CRTH2 previously in clinical development for asthma, has led to the identification of two conformational isomers coexisting in the crystal lattice in a continuous composition range between 89.7%:10.3% and 96.5%:3.5%. These two isomers differ in the chloro-flurorophenyl moiety orientation-the aromatic ring is flipped by 180° in these two isomers. The level of the minor isomer is directly measured through integration of the two peaks in the (19) F solid-state NMR spectrum. The values obtained from the NMR data are in excellent agreement with the degree of disorder of the fluorine atom in the crystal structure, refined using both single-crystal and high-resolution powder X-ray diffraction data.
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http://dx.doi.org/10.1002/jps.24457DOI Listing
July 2015

Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain.

PLoS One 2014 4;9(9):e105895. Epub 2014 Sep 4.

Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.

Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105895PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154897PMC
April 2015

Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.

J Med Chem 2014 Feb 5;57(4):1454-72. Epub 2014 Feb 5.

Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California, 94080, United States.

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
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http://dx.doi.org/10.1021/jm401753eDOI Listing
February 2014

High-throughput 96-well solvent mediated sonic blending synthesis and on-plate solid/solution stability characterization of pharmaceutical cocrystals.

Int J Pharm 2013 Jan 23;441(1-2):356-64. Epub 2012 Nov 23.

Pharmaceutical Research and Development, Small Molecule Process and Product Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.

A 96-well high-throughput cocrystal screening workflow has been developed consisting of solvent-mediated sonic blending synthesis and on-plate solid/solution stability characterization by XRPD. A strategy of cocrystallization screening in selected blend solvents including water mixtures is proposed to not only manipulate solubility of the cocrystal components but also differentiate physical stability of the cocrystal products. Caffeine-oxalic acid and theophylline-oxalic acid cocrystals were prepared and evaluated in relation to saturation levels of the cocrystal components and stability of the cocrystal products in anhydrous and hydrous solvents. AMG 517 was screened with a number of coformers, and solid/solution stability of the resulting cocrystals on the 96-well plate was investigated. A stability trend was observed and confirmed that cocrystals comprised of lower aqueous solubility coformers tended to be more stable in water. Furthermore, cocrystals which could be isolated under hydrous solvent blending condition exhibited superior physical stability to those which could only be obtained under anhydrous condition. This integrated HTS workflow provides an efficient route in an API-sparing approach to screen and identify cocrystal candidates with proper solubility and solid/solution stability properties.
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http://dx.doi.org/10.1016/j.ijpharm.2012.11.020DOI Listing
January 2013

A rapid approach to the preliminary assessment of the physical stability of pharmaceutical hydrates.

J Pharm Sci 2012 Oct 6;101(10):4013-7. Epub 2012 Jul 6.

Pharmaceutical R&D, Small Molecule Process and Product Development, Amgen, Inc., Cambridge, Massachusetts 02142, USA.

Pharmaceutical hydrates have been used as clinical development candidates and in marketed products. The physical stability of hydrates can pose unique challenges to their development because of their particular sensitivity to the moisture levels in their surroundings. By conducting simple experiments early during the form selection phase of a drug candidate's development, a basic understanding of the thermodynamic and kinetic aspects of a hydrate form's stability can be attained that can facilitate the successful navigation of these challenges. Differential scanning calorimetry was used to determine the thermal and kinetic properties of a number of pharmaceutically relevant hydrates. The activation energy (E(a)) of dehydration and dehydration onset temperature (T(onset)) of survey compounds were compiled and analyzed. A significant number of compounds possessed both high E(a) and high T(onset) of dehydration, suggesting that these hydrate crystal forms were particularly stable. The results of these studies suggest that dehydration E(a) and dehydration T(onset) together can be used as early indicators of a crystalline hydrate's physical stability and can alert to potential challenges in developing hydrate crystal forms of drug candidates.
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http://dx.doi.org/10.1002/jps.23257DOI Listing
October 2012

The A to Z of pharmaceutical cocrystals: a decade of fast-moving new science and patents.

Pharm Pat Anal 2012 Jul;1(3):313-27

Alkermes, Inc. 852 Winter Street, Waltham, MA 02451, USA.

From aspirin to zoledronic acid, pharmaceutical cocrystals emerged in the past decade as a promising new weapon in the arsenal of drug development. Resurgence of interest in multicomponent crystal compositions has led to significant advances in the science of cocrystal design and discovery. These advances have built upon crystal engineering, which provides a deep understanding of supramolecular interactions between molecules that govern crystal packing and physicochemical properties of crystalline materials. Concomitantly, the patent landscape of pharmaceutical cocrystals developed rapidly in the last decade. This review presents a broad survey of patents issued in the area of pharmaceutical cocrystals. In addition, the review contains analyses of key patents in the area involving compositions and methodologies. Along the way, the main events of the past decade representing a renaissance of cocrystals of pharmaceutical materials are chronicled. Future directions in the area are discussed in light of key pending patent applications and recent publications of seminal interest.
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http://dx.doi.org/10.4155/ppa.12.29DOI Listing
July 2012

Improved pharmacokinetics of AMG 517 through co-crystallization part 2: analysis of 12 carboxylic acid co-crystals.

J Pharm Sci 2011 Jul 1;100(7):2734-43. Epub 2011 Feb 1.

Amgen, Inc., Cambridge, Massachusetts 02142, USA.

Intrinsic dissolution, powder dissolution, and the pharmacokinetics (PK) of 12 carboxylic acid co-crystals of AMG 517 were determined and compared. Dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). A control dissolution experiment was conducted with the free base in FaSIF plus sorbic acid to compare with the AMG 517 sorbic acid co-crystal (SRA). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. All co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF as well as higher area under the concentration-time curves (AUC) in rat PK investigations compared with the free base. The control dissolution experiment indicates that the increase in dissolution rate of SRA over the free base is not due to the presence of sorbic acid in the dissolution medium. Linear correlation of dissolution rate and AUC among the 12 co-crystals was moderate, indicating that in vitro dissolution is a valuable method to predict whether a co-crystal will improve the exposure of a poorly soluble pharmaceutical ingredient; however, in vivo testing may be required to determine the extent.
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http://dx.doi.org/10.1002/jps.22502DOI Listing
July 2011

Improved pharmacokinetics of AMG 517 through co-crystallization. Part 1: comparison of two acids with corresponding amide co-crystals.

J Pharm Sci 2010 Sep;99(9):3769-78

Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA.

The dissolution and pharmacokinetics (PK) of two carboxylic acid co-crystals (cinnamic acid and benzoic acid) with the corresponding amide co-crystals (cinnamamide and benzamide) of AMG 517 were investigated. Powder and intrinsic dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. The four co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF than the free base. This correlated with a 2.4- to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations. When contrasting the acid to its corresponding amide co-crystal, cinnamamide shows improvement over cinnamic acid, while benzamide and benzoic acid perform similarly.
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http://dx.doi.org/10.1002/jps.22181DOI Listing
September 2010

A novel oxazolidinone antibiotic: RWJ-416457.

Acta Crystallogr C 2010 May 13;66(Pt 5):o249-51. Epub 2010 Apr 13.

Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.

The crystal structure of the antibiotic drug candidate RWJ-416457 (systematic name: N-{(5S)-3-[4-(5,6-dihydro-2H,4H-2-methylpyrrolo[3,4-c]pyrazol-5-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}acetamide), C(18)H(20)FN(5)O(3), which belongs to the first new class of antibiotics discovered in the past 30 years, has been determined at 150 K. Each molecule of this drug donates one hydrogen bond to a neighboring molecule and accepts one hydrogen bond to give (O=C-R-N-H...O=C-R-N-H...)(n) linkages along the b-axis direction. The compound contains a pyrrolopyrazole ring, which, owing to its uncommon structure, has been shown to have particular effectiveness against multi-drug-resistant bacteria.
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http://dx.doi.org/10.1107/S0108270110009339DOI Listing
May 2010

Identification and synthesis of 2,7-diamino-thiazolo[5,4-d]pyrimidine derivatives as TRPV1 antagonists.

Bioorg Med Chem Lett 2009 Jan 13;19(1):40-6. Epub 2008 Nov 13.

Johnson & Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121, USA.

We have identified and synthesized a series of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists. An exploration of the structure-activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several potent TRPV1 antagonists, including 3, 29, 51, and 57. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia with an ED(50)=0.5mg/kg in rats.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.024DOI Listing
January 2009

Celecoxib:nicotinamide dissociation: using excipients to capture the cocrystal's potential.

Mol Pharm 2007 May-Jun;4(3):386-400. Epub 2007 May 12.

TransForm Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts 02421, and Department of Physics & Astronomy, Stony Brook University, Stony Brook, New York 11794-3800, USA.

The cocrystal of celecoxib and nicotinamide (Cel:Nic) was crystallized from chloroform in a 1:1 ratio, and the structure has been solved from powder X-ray diffraction data. The dissolution and solubility of Cel:Nic are medium dependent and can be attributed to differences in conversion of Cel:Nic to celecoxib polymorphs I and III (Cel-I and Cel-III). The presence of low concentrations of surfactants facilitates the rapid conversion of neat Cel:Nic to large aggregates of Cel-III that dissolve more slowly than commercial Cel-III into 1% SDS solution. In contrast, combinations of Cel:Nic with both 1-10% solid SDS and PVP wet rapidly and convert to a mixture of amorphous celecoxib and a micron-sized crystalline celecoxib form IV (Cel-IV), which has recently been shown to be up to 4-fold more bioavailable than marketed Cel-III. More than 90% of the suspended material dissolves within 2 min at 37 degrees C when transferred to 1% SDS solution. This example highlights the importance of exploring the form conversion of cocrystals in aqueous media prior to pharmacokinetic studies, and illustrates the potential of simple formulations to overcome the limitations caused by rapid dissociation of cocrystals and recrystallization of poorly soluble forms in aqueous media.
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http://dx.doi.org/10.1021/mp0700108DOI Listing
August 2007

Hydrates and solid-state reactivity: a survey of beta-lactam antibiotics.

J Pharm Sci 2007 May;96(5):1090-9

TransForm Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts 02421, USA.

Crystalline hydrates of hydrolytically susceptible pharmaceuticals are commonly encountered, and are particularly prevalent in the beta-lactam class of antibiotics. In order to rationalize how the apparent chemical incompatibility between water and beta-lactams is reduced through crystallization, a review of the published literature and available structural information on the solid state stability was undertaken. A search in the CSD yielded a total of 32 crystal structures of water-containing beta-lactams which were examined and classified in terms of hydrogen-bonded networks. In most cases the waters of hydration in the single crystal structures were found to fulfill structural roles and were not sufficiently close in proximity to react with the beta-lactam ring. Published data for the solid-state of several hydrates were also considered. In general, the stability data indicate high thermal stability for the crystalline hydrates. Moreover, even when water molecules are in appropriate proximity and orientation with respect to the beta-lactam moiety for a reaction to occur, the crystalline solids remain stable. The use of the crystal structure information along with computational modeling suggests that a combination of proximal relationships, steric and mechanistic arguments can explain the observed solid-state stability of crystalline beta-lactam hydrates.
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http://dx.doi.org/10.1002/jps.20919DOI Listing
May 2007

Performance comparison of a co-crystal of carbamazepine with marketed product.

Eur J Pharm Biopharm 2007 Aug 28;67(1):112-9. Epub 2006 Dec 28.

TransForm Pharmaceuticals, Inc., Lexington, MA 02421, USA.

The carbamazepine: saccharin co-crystal (1) was studied in terms of a series of attributes, including suitability for multi-gram scale-up, propensity for crystal polymorphism, physical stability, in vitro dissolution and oral bioavailability, with the goal of comparing 1 with the marketed form of carbamazepine (Tegretol). Preparation of 1 was achieved on a 30g scale with a conventional cooling crystallization process from alcohol solution without seeding. The compound is not overtly polymorphic. This finding is in contrast to the form diversity of pure carbamazepine, which has four known polymorphs and a host of solvates, including a dihydrate, which is the stable form in the presence of water. Physical and chemical stability of the co-crystal is also shown to be quantitatively similar to the pure drug in the marketed product (Tegretol). Finally, comparison of oral bioavailability of 1 with Tegretol tablets in dogs shows the co-crystal to be a viable alternative to the anhydrous polymorph in formulated solid oral products. The balance of properties and performance of 1 as a model co-crystal is discussed.
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http://dx.doi.org/10.1016/j.ejpb.2006.12.016DOI Listing
August 2007

Expanding the scope of crystal form evaluation in pharmaceutical science.

J Pharm Pharm Sci 2006 ;9(3):317-26

TransForm Pharmaceuticals Inc. Lexington, MA 02421, USA.

The commentary seeks to provide a brief history and perspective on the importance of crystal forms of pharmaceuticals as a means of achieving performance criteria. The expanding scope of crystal form selection, emergence of crystal engineering in pharmaceutical science and pharmaceutical co-crystals are topics of this brief review.
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March 2007

The predictably elusive form II of aspirin.

J Am Chem Soc 2005 Dec;127(48):16802-3

Department of Chemistry, University of South Florida, Tampa, 33620, USA.

The elusive form II of aspirin has been obtained during co-crystallization experiments with levetiracetam or acetamide, and it has been characterized by IR, DSC, HPLC, and single-crystal X-ray diffraction.
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http://dx.doi.org/10.1021/ja056455bDOI Listing
December 2005

Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients.

Chem Commun (Camb) 2005 Sep 15(36):4601-3. Epub 2005 Aug 15.

Department of Chemistry, University of South Florida, SCA 400, 4202 E. Fowler Avenue, Tampa, Florida, USA.

The carboxylic acid-primary amide supramolecular heterosynthon is exploited for the generation of pharmaceutical co-crystals that contain two active pharmaceutical ingredients that are polymorphic in their pure forms.
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http://dx.doi.org/10.1039/b501304fDOI Listing
September 2005

High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids.

Adv Drug Deliv Rev 2004 Feb;56(3):275-300

TransForm Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, MA 02421, USA.

The concepts of high-throughput (HT) screening and combinatorial synthesis have been integrated into the pharmaceutical discovery process, but are not yet commonplace in the pharmaceutical development arena. Emerging strategies to speed pharmaceutical development and capture solid form diversity of pharmaceutical substances have resulted in the emergence of HT crystallization technologies. The primary type of diversity often refers to polymorphs, which are different crystal forms of the same chemical composition. However, diverse salt forms, co-crystals, hydrates and solvates are also amenable to study in HT crystallization systems. The impact of form diversity encompasses issues of stability and bioavailability, as well as development considerations such as process definition, formulation design, patent protection and regulatory control. This review highlights the opportunities and challenges of HT crystallization technologies as they apply to pharmaceutical research and development.
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http://dx.doi.org/10.1016/j.addr.2003.10.020DOI Listing
February 2004

Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids.

J Am Chem Soc 2003 Jul;125(28):8456-7

Transform Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts 02421-3102, USA.

Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.
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http://dx.doi.org/10.1021/ja035776pDOI Listing
July 2003

Template effects, asymmetry, and twinning in helical inclusion compounds.

Angew Chem Int Ed Engl 2002 Mar;41(6):965-9

Chemistry Department, Kansas State University, 111 Willard Hall, Manhattan, KS 66506, USA.

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http://dx.doi.org/10.1002/1521-3773(20020315)41:6<965::aid-anie965>3.0.co;2-yDOI Listing
March 2002

Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III.

J Am Chem Soc 2002 Sep;124(37):10958-9

TransForm Pharmaceuticals, Inc., 610 Lincoln Street, Waltham, Massachusetts 02451, USA.

Three crystal forms of acetaminophen were prepared and characterized using a newly developed high-throughput crystallization platform, CrystalMax. The platform consists of design software, robotic sample dispensing and handling, and high-throughput microanalytics and is capable of running thousands of crystallizations in parallel using several different methods to drive supersaturation and subsequent crystallization. Additionally, structural models of the elusive third form of acetaminophen will be discussed on the basis of powder X-ray diffraction data. One structure suggested has a bilayer motif, held together by O-H...O(H) hydrogen bonds, and helps explain the difficulty associated with preparing this form from solution.
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http://dx.doi.org/10.1021/ja020751wDOI Listing
September 2002

Unanticipated guest motion during a phase transition in a ferroelastic inclusion compound.

J Am Chem Soc 2002 Mar;124(10):2094-5

Department of Chemistry, Kansas State University, Manhattan, Kansas 66506, USA.

Urea inclusion compounds (UICs) have been used as tools to understand ferroelastic domain switching and molecular recognition during crystal growth. Although the vast majority of UICs contain helical arrangements of host H-bonds, those containing guests with the formula X(CH(2))(6)Y (X, Y = Br, Cl, CN, NC) adopt an alternative P2(1)/n packing mode in which the host molecules exist as stacked loops of urea hexamers. Such structures may be further separated into two classes, ones distorted away from hexagonal symmetry along [100] (Br(CH(2))(6)Br, Br(CH(2))(6)Cl, and Cl(CH(2))(6)Cl) and those distorted along [001] (e.g. NC(CH(2))(6)CN). In each of these systems, guests exist as equilibrium mixtures of gauche conformers whose populations control the direction and magnitude of the observed distortion. Such UICs are potentially ferroelastic, but the n-glide requires that domains are not related by a simple rotation-translation mechanism as in the helical systems. Ferroelastic (degenerate) domain reorientation would necessitate a large-scale reorganization of the urea framework and rupture of numerous H-bonds. Coupled with distortions of 2 to 10%, this mechanism-based barrier to domain switching has precluded observation of this phenomenon. To prepare ferroelastic UICs with minimal distortions from hexagonal symmetry, attempts were made to form solid solutions of UICs containing guests from the two classes. This failed, however: solid solution formation of the stacked loop form is usually possible within a series (e.g. with Cl(CH(2))(6)Cl and Br(CH(2))(6)Br), but not between series (e.g. Cl(CH(2))(6)Cl and NC(CH(2))(6)CN). Crystals of Cl(CH(2))(6)CN/urea, in which a single guest contains substituents from each class, are distorted along [001] by only 0.5% from hexagonal symmetry at 298 K and exhibit ferroelastic domain reorientation at high forces. At -66 degrees C, Cl(CH(2))(6)CN/urea undergoes a topotactic phase transition that is unexpectedly nontopochemical. The structure of the low-temperature phase, including the orientation of the methylene chain, closely matches the structures of UICs distorted by 10% along [100] (e.g. Cl(CH(2))(6)Cl/urea). In this transition, small conformation changes of guests give rise to large-scale guest translations of approximately 5.5 A down the channel axis, even though an analogous gauche-to-gauche jump is well established in closely related materials that adopt either high- or low-temperature forms (e.g. NC(CH(2))(6)CN/urea, Cl(CH(2))(6)Cl/urea). The large guest displacement during this transition explains the difficulty in preparing solid solutions of the P2(1)/n form with guests of formula X(CH(2))(6)Y from two different series (e.g. Cl(CH(2))(6)Cl and NC(CH(2))(6)CN). This failure arises not from the different orientations of guest-induced strain, but from preferential occupation of different sites along the channel by the two types of guests. The subtlety of this process and of the interactions involved highlights the difficulty in using simple considerations of isomorphism to design new materials.
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http://dx.doi.org/10.1021/ja010327fDOI Listing
March 2002