Session 2: Particle Engineering & DS-DP Co-Processing Archives - Pharma Crystallization Summit

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.

The post Examples of Particle Engineering to Improve Patient Outcomes and Product Manufacturing appeared first on Pharma Crystallization Summit.

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.

The post Crystal Habit Modifications and Spherical Crystallization Design in Solution appeared first on Pharma Crystallization Summit.

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.

The post Challenges and Opportunities in Optimizing Mechanical Properties of Drugs by Incorporating Excipients appeared first on Pharma Crystallization Summit.

Bridging the Gap between Drug Substance and Drug Product Processing via Co-Processing

wpadm — Tue, 16 Jun 2020 02:28:44 +0000

Dr. Jian Wang SVP J-Star Research – a Porton Company Between API or drug substance (DS) processing and drug product (DP) processing, there is a conventional gap (or wall) that adds additional time and efforts to new drug development programs and limits special formulation development. It is common for desired DP performance(s) to request the DS meeting specs of particle size distribution, morphology, bulk density, flow property, hygroscopicity control, and others aside from meeting specs of purity, residual solvent content, polymorph ID/content, etc.. Even for a DS delivered with required quality attributes, after significant developmental efforts, challenges still remain in DP processing. Such as, the needs for further milling (either de-lumping or micronization) of DS, accurate subdivision into vials or capsules, even blending with excipients, instability during compression, and more and more often, the needs for solubility or dissolution enhancement, controlled release (slow or fast or in combination), etc.. Many of such technical hurdles in DS and DP developments and processing can be addressed with much greater efficiency through DS-DP co-processing. In solid dosage processes, DS is generally blended with excipients via wet or dry granulation, which can be better or more effectively handled by co-processing. Co-processing is a relatively new area of particle engineering in which commonly used excipients can be combined with the API in a more deliberate and controlled manner to design a pharmaceutical composite material (PCM)1,2. This approach combines two or more materials in a specific way in order to produce a composite material with improved physical or chemical properties. A PCM can be designed to resolve some of the common issues related to solid dosage production such as material flow, stability, compactibility, release profile, bioavailability, solubility and dissolution3, food effect, content uniformity, taste, and even containment issues related to potent or toxic compounds. Cases and on-going efforts in DS-DP co-processing at the Center for Pharma Crystallization (CfPC) will be discussed, highlighting the benefits of bridging the gap between DS and DP via co-processing. 1. M. Saffari, A. Ebrahimi, T. Langrish, A novel formulation for solubility and content uniformity enhancement of poorly water soluble drugs using highly porous mannitol. Eur. J. Pharm. Sci., 83(2016), pp 52-61 2. Nima Yazdanpanah, Christopher J. Testa, Siva R. K. Perala, Keith D. Jensen, Richard D. Braatz, Allan S. Myerson, and Bernhardt L. Trout “Continuous Heterogeneous Crystallization on Excipient Surfaces” Crystal Growth and Design, 2017, 17, 3321-3330 3. Qian, et al. J Pharm Sci. 2010, 99(7), 2941-2947.

The post Bridging the Gap between Drug Substance and Drug Product Processing via Co-Processing appeared first on Pharma Crystallization Summit.