2021 Abstracts Archives - Pharma Crystallization Summit

Potentials and Technologies to Increase Success Rate of Polymorph Screening

wpadm — Tue, 16 Jun 2020 18:20:37 +0000

Moderator: Dr. Alfred Lee Principal Scientist Merck Research Laboratories Coming soon

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Overcoming Industrial Challenges in Implementation of Crystallization Technologies

wpadm — Tue, 16 Jun 2020 18:19:56 +0000

Moderator: Dr. Kevin Girard Associate Research Fellow Pfizer Coming soon

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Realizing Regulatory Challenges in Applying Crystallization Technologies

wpadm — Tue, 16 Jun 2020 18:18:12 +0000

Moderator: Dr. Christopher Burcham Senior Engineering Research Advisor Eli Lilly and Company

Coming soon

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Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264): A Solid-State Chemistry Perspective

wpadm — Tue, 16 Jun 2020 02:36:49 +0000

Alfred Y. Lee Department of Analytical Research & Development Merck & Co., New Jersey USA Keywords: Green Manufacturing, Gefapixant Citrate, Solid-State Chemistry, crystal structure prediction Gefapixant citrate (or MK-7264) is a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. It has demonstrated significant efficacy in recent Phase 3 clinical trials in reducing the frequency of cough in patients with refractory chronic cough after 12 weeks of treatment compared to placebo. A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate. The newly developed commercial process features many advantages including low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced active pharmaceutical ingredient (API) costs. This presentation provides a solid-state chemistry perspective on the development of a commercial manufacturing process for gefapixant citrate. Key innovations that will be discussed are: (1) exploitation of a cocrystal that enabled chemical purification and enhance the physical properties of a regulatory starting material; (2) utilization of crystal structure prediction (CSP) across the chemical synthesis to ensure that products are launched with the best chemical processes; (3) manipulation of a physical form for crystallization selectivity to purge chemical impurities; (4) a novel salt metathesis approach to consistently deliver the correct API salt form in high purity; and (5) navigation of a complex solid form landscape through knowledge of a process phase diagram.

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What Solid Form Should I Choose?

wpadm — Tue, 16 Jun 2020 02:35:30 +0000

Ann Newman Pharmaceutical Consultant Seventh Street Development Group The solid form of an active pharmaceutical ingredient (API) used in development has become an important aspect of drug development based on possible issues with manufacturability, solubility, bioavailability, and stability differences between materials. A variety of solid forms can be investigated in screening studies, including polymorphs, salts, cocrystals, amorphous, and amorphous dispersions. The next step after finding the forms is collecting relevant data to choose the best form for the targeted dosage form and development plan. This usually includes more in-depth experiments with solubility, physical and chemical stability, and possible process induced transformations during API crystallization or formulation. This talk will discuss properties to consider when choosing a form, as well as methods used in the industry for comparison. Case studies that illustrate the selection process will be presented, and examples of using different forms in various types of formulations for lifecycle management will also be discussed.

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Understanding and Controlling the API Form/Powder Property Risks in Drug Substance and Product Processes

wpadm — Tue, 16 Jun 2020 02:34:31 +0000

Dr. Shawn Yin Scientific Director, Materials Science and Engineering, Drug Product & Development Bristol-Myers Squibb Co. Abstract It is well known that some key drug substance physical properties, like crystal form, crystallinity, size, morphology, etc., can be altered during drug substance and/or product processes, and potentially during the product shelf life. Therefore, acquiring a good knowledge of how both the DS and DP process impacting on these critical product quality attributes is one of the key development activities, aiming at ensuring a success product development and bringing a robust product to the market. This presentation described, via real development/manufacturing examples, several risk factors including regulatory risk of DS/DP process induced API physical changes. These risks are assessed based on physical characteristics of material single crystal structures, surface/bulk physical characterizations and their relevant biopharmaceutical properties. The impacts of these risks on DS/DP CMC activities, product quality and patients are also discussed.

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Absolute Structure Determination of API Molecules by MicroED analysis of Cocrystals formed based on Cocrystal Propensity Prediction Calculations

wpadm — Tue, 16 Jun 2020 02:33:14 +0000

Chandler Greenwell Applications Scientist XtalPi Harsh Shah Senior Scientist J-Star) Jessica Bruhn Principal Scientist NanoImaging Services Of the 35 small molecule drugs approved in 2020, 43% were chiral compounds formulated as enantiopure products. For most chiral small molecule drugs, only one enantiomer is biologically active, while the other enantiomer can potentially lead to unwanted side-effects/toxicity (e.g. thalidomide). Therefore, it is critical that researchers establish ways to purify only the desired enantiomer and use structural characterization techniques to understand which enantiomer is biologically active. Historically, single crystal X-ray diffraction (scXRD) has been the gold standard for establishing the absolute configuration of active pharmaceutical ingredients (APIs), either directly from the measured intensities or by co-crystallization with a chiral probe. Unfortunately, this technique is limited by the need to grow suitably sized crystals, which can be challenging for many APIs. Here, we present a method for obtaining absolute configuration from chiral co-crystals that are too small for scXRD by using microcrystal electron diffraction (MicroED). In order to streamline this approach, we have also employed computational methods to guide co-crystal formation. These computational methods combine a conductor-like model for realistic solvents (COSMO-RS), machine learning (ML) and pKa considerations to virtually screen a large list of potential co-formers. The top co-former hits were then employed in cocrystal screens and potential co-crystals were characterized by light microscopy, X-ray powder diffraction and NMR. Crystalline material was then sent for MicroED structure determination without the need to optimize for the growth of large crystals, resulting in a rapid structure determination and establishment of the absolute configuration of the API. This strategy was employed to determine the absolute configuration of two pharmaceutical compounds: Finafloxacin and Ipragliflozin.

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Examples of Particle Engineering to Improve Patient Outcomes and Product Manufacturing

wpadm — Tue, 16 Jun 2020 02:32:22 +0000

Christopher L. Burcham Senior Engineering Research Advisor Eli Lilly and Company Key Words: Particle Engineering, Crystallization, Solubility Enhancement Pharmaceutical products are held to high standards of quality, necessary to ensure that a patient receives medicines that are safe and effective. Regulatory bodies also expect and require that pharmaceutical manufacturers are able to produce medicines in a way that is reliable ensuring there is minimal risk to disrupting the supply of medicines to patients. The solid form of an active pharmaceutical ingredient can directly impact the performance of a solid oral dosage form. The physical properties of the drug substance can also negatively impact the ability to manufacture drug product. Control of and improvements to the physical properties of the drug substance can be achieved through crystallization process design, improving downstream manufacturing and ensuring optimal product performance. However, in some cases for poorly soluble drugs, improving the physical properties of a crystalline drug substance is not enough to ensure adequate product exposure. In these cases, alternative particle engineering techniques can be utilized to increase the solubility of the drug substance offering increased bioavailability. Examples of applications of particle engineering techniques to improve processability as well as product performance will be presented.

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Crystal Habit Modifications and Spherical Crystallization Design in Solution

wpadm — Tue, 16 Jun 2020 02:31:33 +0000

Prof. Junbo Gong Professor, School of Chemical Engineering and Technology Tianjin University KEY WORDS: Crystal habit control, Mechanism of crystal and particle growth, Additive and Solvent effect, Molecular dynamic simulations, Spherical crystallization, Design strategy In the solution crystallization, organic crystals are generally assembled based on hydrogen bonds between molecules, as hydrogen bonds have directionality, organic crystals often grow into needle-like or lamellar crystal habits, with low bulk density and poor flowability. However, due to the lack of in-depth understanding of crystal growth mechanism and the impeccable crystal habit prediction model, crystal habit optimization relies heavily on empirical operation with high cost and low efficiency. Aiming at the problems of poor crystal habit and low purity of D-PC, the crystal habit regulation of D-PC was realized based on the crystal form control. The crystal forms and habits of D-PC at different solvents were fully characterized, and calcium Dpantothenate tetramethanol monohydrate (D PC·4MeOH·H2O) with block habit and low solvent removal temperature, was considered as the suitable crystal form for industry production. The phase transformation from Calcium D-pantothenate methanol solvate (D-PC·MeOH) to·D-PC·4MeOH·H2O was monitored by in situ ATR-FTIR and Raman spectroscopy, the results demonstrated that the rate-controlling step was the nucleation and growth of D-PC·4MeOH·H2O. The desolvation process of DPC·4MeOH·H2O was studied by variable-temperature PXRD and Hot Stage Polarized Microscopy, and the solvent-free amorphous D-PC with block habit was obtained. The molecular dynamics simulations were performed to reveal the temperature role in the phase transformation process at the molecular level. This work provides a layout to optimize the crystallization of D-PC in the future. The effects of the concentration and the chain length of sodium alkylsulfate (SDS), sodium alkylsulfonate (SLS), and sodium alkyl benzenesulfonate (SDBS) on the growth of VB1 were studied by single crystal growth experiments. It was found that SDS and SDBS exhibited significant inhibitory effects on VB1 crystal growth along the axial than radial axis, therby modifying VB1 from long rod to block; while SLS had a very slight inhibition on VB1 crystal growth, and exhibited almost no effect on VB1 habit. The mechanism of additive in regulating VB1 crystal habit was proposed by combining experiment and molecular dynamics simulation; all the three kinds of additives showed slight inhibitory effects on VB1 crystal growth by hindering the diffusion of solute. However, compared with SLS, SDS and SDBS can selectively adsorb on the VB1 crystal surface along axial axis and inhibiting its growth through strong electrostatic and hydrogen bonding. The crystal growth of VB6 in the absence and presence nonionic and ionic surfactants was investigated by single crystal growth experiments and theoretical calculations. In experiments, VB6 crystals exhibited block-like habit in aqueous and non-ionic surfactant solution, while needle-like VB6 crystals were observed in ionic surfactant solutions. The mechanism of surfactants in modulating VB6 crystal morphology was proposed by calculating the electrostatic potential of the surfactants; the preferential adsorption of sodium dodecyl sulfate (12 SDS) on the radial (010) surface inhibiting its growth over the axial (100) surface results in high aspect ratio of VB6 crystals. Hexadecyl trimethyl ammonium bromide (CTAB) enhances both (100) and (010) surfaces growth by promoting Cl- ions integration to the surfaces. Dodecyl dimethyl betaine (DDMB) hinders (010) surface growth by surface adsorption while promotes (100) surface growth by accelerating Cl- integration. In addition, Tween 80 has a slight inhibitory effect on (100) and (010) crystal growth by hindering solute transport through steric hindrance. The constant chemical potential dynamics simulations (CμMD) was constructed to quantitatively investage the crystal growth rate of INH in different solvents, and uncover the growth mechanism of INH. Experiments showed isoniazid grew as needlelike crystals in water, while in alcohols such as methanol, ethanol and isopropanol, it exhibited a rod-like crystal habit. The simulation results revealed a rough growth mechanism for the fast growing (110) surface along the of INH crystal, and bulk transport of the solute was the limiting-step, the relative growth rate of this surface decreased from methanol, ethanol to isopropanol. On the other hand, the slow growing (002) surface along the axial direction appeared to follow a stepwise growth mechanism, with a surface integration step chiefly controlling the growth. The relative growth rate of this surface increased from methanol to ethanol and isopropanol. Spherical crystals are special crystalline products with enhanced performance,unique functions and extra values. It has become a hot spot in the high-tech fields of pharmaceutical, food, daily chemical, fertilizer, and military industries. However, it is still challenging for preparing the given crystals into spheres with desired performance.To solve this issue, three universal strategies were developed for designing spherical crystallization processes, i.e. spherical agglomeration, spherulitic growth and multicluster growth. Strategies of selecting ternary solvent systems and process control for spherical agglomeration were developed. The strategy of selecting solvent systems emphasizes wettability as the key parameter which is quantitative estimated by the Lifshitz-van der Waals acid-base approach. Valid systems therefore are selected in the first place while invalid ones are removed effectively according to the wettability difference. With the aid of the strategy, 4 valid solvent systems for cefotaxime sodium from 720 solvent combinations and 24 valid ones for benzoic acid from 2184 solvent combinations were selected successfully without missing the reported systems. The strategy of process control is designed with the independent size space and shape space, so that the quantitative relationship between process parameters and morphology of spheres can be clearly established. This strategy successfully tuned the spherical agglomerate of benzoic acid from 1000-5000 μm avoiding wide size distribution and fragments by the conventional strategy. A strategy of designing spherulitic growth process was developed. It predicts the critical superstation of spherulitic growth with the rough growth model. Based on the strategy, spherulites of clopidogrel hydrogen sulfate (Form I) and fructose were successfully prepared. In the case study of clopidogrel hydrogen sulfate, it indicated the theoretical drawbacks of the single solvent system designed by trial-and-error method in literature, and designed the mixture system achieving the targets of spherical shape, no crystal form transformation, and no jelly-like phase. A novel spherical crystallization method was developed. According to crystalline cluster growth on crystal surface and attrition effect of agitation, it prepares spherical crystals in a single solvent (water) system under a common condition of supersaturation. Its strategy was developed with multi-cluster growth model and agglomerate size model.Spherical crystals of potassium chloride, sodium chloride and cesium iodide were prepared successfully by the strategy.

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Challenges and Opportunities in Optimizing Mechanical Properties of Drugs by Incorporating Excipients

wpadm — Tue, 16 Jun 2020 02:29:37 +0000

Prof. Calvin Changquan Sun Professor, Director of Graduate Studies, and Associate Department Head, Department of Pharmaceutics University of Minnesota Key Words: Flowability, tabletability, punch sticking, crystal engineering, particle engineering Purpose: The manufacturing of high quality tablets requires certain powder mechanical properties, which are often not exhibited by drug substances. Common problems during tablet development include poor flowability, low tabletability, and punch sticking. The ability of traditional approaches of formulation screening and process control in addressing these problems are often limited. In contrast, crystal and particle engineering can address such challenges more effectively by designing drug-excipient composites with unique structures and desired properties. Methods: Coating a small amount of discrete layer of nano guest particles on fine drug particles profoundly reduces cohesion of a powder,1 which significantly improves powder flowability.2 This flow-enhancing technique is broadly applicable because it is based on the particle contact physics that reliably reduces cohesion of a powder. Nano-coating can be attained using economical and continuous processes suitable for pharmaceutical manufacturing, such as comilling.3 The problem of poor tabletability of drugs is usually caused by insufficient areas of bonding among drug particles, due to the limited extent of permanent deformation of particles during the compression process.4 Accordingly, there is the opportunity for overcoming the poor tabletability problem by forming drug-excipient composite particles capable of forming a sufficiently large bonding area by compression. This can be achieved by 1) coating drug particle with a layer of deformable polymer,5 2) increasing plasticity of drug crystals through modifying crystal structure by incorporating in crystal lattice a pharmaceutically acceptable excipient, such as water and other coformers.6, 7 In addition, crystalline drug-excipient composites can modulate punch sticking propensity through modifying both mechanical properties and surface functional groups of drug crystal.8 Results: The discussion of fundamental materials science underlying each problem lays a foundation for identifying extremely effective crystal and particle engineering strategies for preparing drug-excipient composites. Such engineered drug particles exhibit optimal structures and properties, which subsequently lead to robust manufacturing of high quality tablet products. Conclusion: The concept of Materials Science Tetrahedron is the main thread of this presentation.9 It guides effective API engineering to attain optimal properties, beyond these discussed here, to overcome problems and enable successful drug product development. References 1. Kendall, K. Adhesion: Molecules and mechanics. Science 1994, 263, 1720-1725. 2. Yang, J.; Sliva, A.; Banerjee, A.; Dave, R. N.; Pfeffer, R. Dry particle coating for improving the flowability of cohesive powders Powder Technol. 2005, 158, 21-33. 3. Chattoraj, S.; Shi, L.; Sun, C. C. Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano‐silica through comilling. J. Pharm. Sci. 2011, 100, (11), 4943-4952. 4. Sun, C. C. Decoding Powder Tabletability: Roles of Particle Adhesion and Plasticity. Journal of Adhesion Science and Technology 2011, 25, (4-5), 483-499. 5. Shi, L.; Sun, C. C. Transforming powder mechanical properties by core/shell structure: Compressible sand. J. Pharm. Sci. 2010, 99, (11), 4458-4462. 6. Sun, C. C.; Hou, H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization Crystal Growth & Design 2008, 8, (5), 1575-1579. 7. Hu, S.; Mishra, M. K.; Sun, C. C. Twistable Pharmaceutical Crystal Exhibiting Exceptional Plasticity and Tabletability. Chem. Mater. 2019, 31, (10), 3818-3822. 8. Paul, S.; Wang, C.; Wang, K.; Sun, C. C. Reduced Punch Sticking Propensity of Acesulfame by Salt Formation: Role of Crystal Mechanical Property and Surface Chemistry. Molecular Pharmaceutics 2019. 9. Sun, C. C. Materials science tetrahedron—A useful tool for pharmaceutical research and development. J. Pharm. Sci. 2009, 98, (5), 1671-1687.

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