- Email: [email protected]
Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression
Journal of Pharmaceutical Sciences xxx (2018) 1-7
Contents lists available at ScienceDirect
Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org
General Commentary
Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression Sayantan Chattoraj 1, *, Changquan Calvin Sun 2, * 1 2
Drug Product Design and Development, GlaxoSmithKline Pharmaceuticals R&D, Collegeville, Pennsylvania 19426 Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, University of Minnesota, Minnesota 55455
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 September 2017 Revised 19 November 2017 Accepted 28 November 2017
Continuous manufacturing of tablets has many advantages, including batch size flexibility, demandadaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process. © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
Keywords: continuous manufacturing direct compression crystal engineering particle engineering formulation design Quality-by-Design compression flow
Introduction The state of pharmaceutical tablet manufacturing is witnessing a strategic shift in the recent years. There is a conscious effort across the pharmaceutical industry to transform the traditional and, somewhat, empirical pharmaceutical development process into a science-based approach that is focused on product quality and process robustness, as stipulated by the Quality-by-Design (QbD) framework.1-3 The paradigm of a QbD filing for regulatory approval of new drug products is no longer a “nice-to-have” for the pharmaceutical industry, as illustrated by the recently published policy from U.S. Food and Drug Administration, MAPP 5016.1, which outlines its expectations for applying International Council on Harmonization ICH Q8(R2), Q9, and Q10 during product development and regulatory review of new drug applications.4 Fundamental to the successful QbD implementation in pharmaceutical
* Correspondence to: Sayantan Chattoraj (Telephone: þ1 610-917-4634; Fax: þ1 610-917-5935) and Changquan Calvin Sun (Telephone: þ1 612-624-3722; Fax: þ1 612-626-2125). E-mail addresses: [email protected] (S. Chattoraj), sunx0053@umn. edu (C.C. Sun).
development is building the understanding of the relationship between the structure and properties of materials as well as manufacturing process relevant to the quality of drug products.5 In addition to embedding the QbD principles, the switch from the traditional batch manufacturing into continuous manufacturing, operated with integrated modelebased controls, is another aspect of pharmaceutical development that is receiving significant attention. Continuous manufacturing is defined as a process where a continuous flow of input raw materials is transformed into finished products under a state of control, with any product manufactured outside the control limits diverted.6,7 Continuous manufacturing of pharmaceuticals has recently been categorized as an advanced manufacturing technology area of emerging priority by the U.S. Federal Government.8 Continuous manufacturing offers a wide spectrum of advantages and has the potential to significantly reduce operational costs and capital costs by: (a) increasing efficiency and shortening development and manufacturing timelines, (b) significantly reducing product losses, (c) reducing operational footprint, (d) increasing consistency of the manufacturing process, and (e) enhancing quality of the product.6,7,9 A true continuous manufacturing line requires every step in the process to be continuous and seamlessly integrated. In many cases,
https://doi.org/10.1016/j.xphs.2017.11.023 0022-3549/© 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
2
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
the design of the continuous line is semicontinuous, having a combination of continuous and batch process steps. Tablet manufacturing by both granulation (wet or dry) and direct compression are amenable to continuous manufacturing. A twin screw granulator or a continuous high shear granulator enables continuous wet granulation.10,11 Continuous dry granulation can be achieved using roller compaction, which is inherently a continuous process. These continuous processes can be integrated with other unit operations to form a continuous manufacturing line. However, direct compression is the most suitable process for continuous manufacturing of pharmaceutical tablets, because of the reduced number of unit operations that need to be integrated for continuous manufacturing. In this case, the input powder blend is directly transformed into a tablet without any intermediate process steps of granulation, drying, and granule size reduction. In addition to the shortened manufacturing time, the reduced number of manufacturing steps, and thus fewer critical process parameters to monitor, ensures process robustness and consistent quality of drug products. Finally, direct compression also eliminates under- or over-granulation problems associated with any granulation process. These advantages have led to a heightened recent interest in the strategies to enable continuous direct compression in both the industry and academia.12-16 The 2 fundamental material properties that impact the manufacturability of tablets are powder tabletability and flowability. The key impediment in the implementation of continuous direct compression is often the sub-optimal compression and flow properties of the active pharmaceutical ingredient (API). The loading of API in a majority of pharmaceutical tablet formulations usually falls in the 10%-80% range depending on the dose. A wider range may be expected if all tablets are considered. At that level, the API compression and flow properties will influence final product manufacturing robustness, especially if the drug loading in the formulation is very high. Therefore, API engineering with the objective of improving the compression and flow characteristics is an effective strategy to enable continuous tablet manufacturing by direct compression, eliminating the need of using significant quantities of excipients to address compression and flow deficiencies of API. The objective of this commentary is to outline API engineering strategies to enhance the powder compression and flow properties of pharmaceutical materials. The current understanding of the fundamental relationships between the structure of materials and their compression and flow properties is summarized. Of course, these engineering strategies are equally applicable to enhance manufacturability during traditional batch processes. Powder Compression The Physics of Powder Compression For a given material, the net mechanical strength of tablets directly depends on the bonding area formed between particles due to permanent particle deformation.17 Tablets would retain integrity only if an adequate area of the interparticulate bonding is preserved after the removal of the compression stress at the conclusion of the compression cycle. The development of bonding area among particles is influenced by particle size, shape, surface texture, moisture content, as well as crystal mechanical properties, which are influenced by crystal structure.17 When the total bonding area is the same, tablets with higher bonding strength are stronger. It is the interplay between bonding area and bonding strength that dictates the tablet compression properties of a powder.18 Thus, particle or crystal engineering for improving bonding area, bonding strength, or both can effectively solve problems related to tablet compression.
To effectively design appropriate crystal and particle engineering strategies for improving the compression properties of an API by influencing bonding area and bonding strength of materials, it is important to understand the fundamental relationships among a material's structure, mechanical deformation, and compression properties.19-21 For a solid material, the key mechanical deformation mechanisms under the application of an external mechanical stress include elastic deformation, plastic deformation, viscoelastic deformation, and fragmentation. Elastically deformed particles undergo complete recovery once the external stress is removed. For perfectly elastic materials, the contact area between particles developed during compression is lost after stress removal. Powders of such materials cannot form intact tablets by compression. For this reason, materials with high elasticity have poor powder compression properties and tend to laminate on decompression due to insufficient bonding area as a result of extensive elastic recovery. Plastic deformation is the most important mechanism for creating a permanent bonding area under compression stress. Irreversible plastic deformation is necessary for retaining the bonding area during the decompression phase of powder compaction and, therefore, for producing robust tablets. Since elastic deformation is inevitable, the compression performance of a powder is largely determined by the relative magnitude of the elastic and plastic deformation. The plasticity of crystals depends on the crystal packing.19,22,23 It has been well documented in the literature that the presence of rigid flat molecular layers in crystals enhances the compression properties of materials by increasing plasticity. These flat layers serve as active slip planes, which are crystallographic planes that have the weakest inter-planar interactions in a crystal. These in turn allow facile movement of dislocations in crystals under mechanical stress, a prerequisite for plastic deformation. A well-known pharmaceutical example of the relationship between crystal structure, plasticity, and powder tabletability is acetaminophen. Acetaminophen polymorph I, having a corrugated herringbone (zig-zag) crystal packing, displays extremely poor powder compression properties. However, acetaminophen polymorph II exhibits flat hydrogen-bonded layers and higher plasticity compared with polymorph I. Consequently, polymorph II exhibits superior compression properties to polymorph I.24 The effectiveness of improving tabletability through enhancing crystal plasticity by introducing flat rigid layered crystal structure is also illustrated in several other polymorphic systems.25-27 Contrary to flat slip layers, a crystal with molecules packed in a 3dimensional hydrogen-bonded network structure exhibit more resistance to plastic deformation, and thereby have poor compression properties.19 When multiple mechanisms of slip are possible in a crystal, crystal plasticity is further improved compared with the simple layered structure. An example of such a material is theophylline, whose crystal structure has flat layers that are formed by stacking hydrogen-bonded V-shaped rigid columns. Slipping between columns is even easier than between rigid layers. In addition, columns between adjacent layers are oriented at an angle of 111.61, thus making them crystal capable of accommodating the compression stress at 2 different orientations to further improve plasticity. This results in exceptional tablet compression properties.19 Other examples of good crystal plasticity and tabletability corresponding to such stacking column structures were also reported.28 Recent work has suggested that ladder-like molecular packing in theophylline monohydrate is responsible for its superior plasticity to theophylline anhydrate.29 Such understanding of the fundamental relationship among the structure, mechanical properties, and tableting behavior at the crystal and tablet levels can now be applied to tailor the compression properties of APIs by crystal and particle engineering.
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
Engineering Strategies to Improve Powder Compression Crystal Engineering Strategies Directing crystallization of an API to a crystal form with structures more amenable to plastic deformation, such as rigid flat layers and layers of stacking columns, can significantly improve the compression properties of otherwise poorly compressible APIs to enable the direct compression process. This strategy, although effective, only has limited application in pharmaceutical development because the choice of a polymorph is often driven by the thermodynamic stability, not by mechanical properties. However, this dilemma can be suitably addressed through forming multicomponent crystals, for example, salts or cocrystals, which allow development of a crystal form exhibiting both suitable mechanical properties and stability.30-33 Structural features that promote tabletability, identified in polymorphic systems, are equally effective in enhancing tabletability of multicomponent crystals. In cases where changing the crystal form is not an option due to the advanced phase of the project in the development lifecycle, other crystal engineering approaches to enhance tablet compression while preserving the crystal form may be needed. Some examples of such approaches include the modification of the crystal habit or morphology to enhance the tabletability,34 and co-processing to balance the material deformation mechanics to achieve optimum tablet compression properties. Table 1 provides illustrative case studies where crystal engineering approaches have been successfully applied to significantly improve the compression properties of pharmaceutical powders. Conversely, any crystal structure modification of APIs that limit plastic deformation by introducing herringbone crystal packing or 3-dimensional hydrogen-boded networks can severely deteriorate the compression properties of pharmaceutical powders.19,37 Also, summarized in Table 1 are the mechanisms by which the compression enhancement is brought about through increased bonding area, bonding strength, or both. Although the accurate quantitation of bonding area and bonding strength is challenging, the qualitative understanding of the relationship among crystal structure, mechanical properties, and tabletability is sufficiently
3
advanced to guide crystal engineering to improve the tabletability of APIs. Our experience is that poor tabletability of API, provided bonding strength is sufficient, is usually solved by increasing crystal plasticity, which leads to a larger bonding area on tablet compression. This implies that bonding strength for most molecular crystals is indeed similar, and at least not significantly different to make enhancing bonding area by improving crystal plasticity ineffective. Particle Engineering Strategies In addition to crystal engineering, particle engineering is another effective strategy to overcome tableting problems of pharmaceutical materials. An effective particle engineering approach to enhance powder compression is surface coating of particles with plastically deforming materials, such as polymers. It has been shown that particle surface coated with plastically deforming materials can render superior tabletability to an otherwise non-compressible elastic powder, as demonstrated with both sand and elastic beads.38,39 For a pharmaceutical example, the elastic polymorph I of acetaminophen had significantly improved tablet compression properties when coated with the plastic polymer hydroxypropyl cellulose.40 Powder Flow The Physics of Powder Flow Another key material property important for ensuring manufacturing robustness of tablets is powder flow. Poor flow of powders is a major concern during pharmaceutical development and scale up because it causes variation in tablet properties as well as poor content uniformity. The physics of powder flow under gravity involves the interplay between 2 universal forcesdinterparticle cohesion, primarily van der Waals forces and gravitational force. While gravity favors powder flow, the attractive cohesive force hinders particle separation that is necessary for powder flow to initiate. Any structural feature that allows gravity to dominate over cohesion favors powder flow. Gravity
Table 1 Illustrative Case Studies of Improving Compression Properties of Pharmaceutical Materials by Crystal Engineering Approaches Crystal Engineering Approach
Illustrative Case Study
Mechanism of Compression Improvement
Reference
Polymorphism
Influence of crystal structure on the tableting properties of sulfamerazine polymorphs: tabletability of polymorph I of sulfamerazine is significantly better than polymorph II. Molecular packing in polymorph I occurs in flat un-corrugated layers, which act as slip planes favoring plastic deformation, while corrugated molecular layers in polymorph II make plastic deformation more difficult Improving compression properties of caffeine by cocrystallization: compression properties of caffeine can be improved by forming cocrystal with methyl gallate. Cocrystallization introduces flat slip layers in the crystal lattice of caffeine-methyl gallate cocrystal Improving compression properties of acetaminophen through formation of hydrochloride salt: Acetaminophen polymorph I shows extremely poor compression. By forming a HCl salt monohydrate of acetaminophen, almost a 200-fold increase in tablet tensile strength is possible Improving compression properties of p-hydroxy benzoic acid by forming monohydrate: the introduction of water in between corrugated layers in the crystal structure of p-hydroxy benzoic acid facilitates plastic deformation resulting in better tabletability of the monohydrate. In addition, the lattice energy of the crystal increases because of the formation of an extensive hydrogen bond network in monohydrate crystal structure
Bonding area enhancement through increasing crystal plasticity by introduction of flat slip planes
25
Bonding area enhancement through increase in plastic deformation by introduction of flat slip planes
30
Bonding area enhancement through increase in plastic deformation by the introduction of flat slip planes
35
Bonding area enhancement through increase in plastic deformation Bonding strength enhancement by increased lattice energy by forming a 3-dimensional hydrogen bonding network
36
Cocrystallization
Salt Formation
Hydrate Formation
4
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
typically can dominate over cohesion for large particles.41 When the particle size is reduced to a critical average particle size of ~30 mm for organic powders, flow issues are often encountered as interparticle cohesion starts to dominate over the gravitational force.42 This is one reason why powder flow of micronized APIs is usually poor. Powder flow is also sensitive to particle shape and surface texture. Generally, more spherical particles flow better than elongated particles43 or particles with smoother surfaces.44 The conventional way to address the flow problem in the pharmaceutical industry is to increase the particle size by granulation. However, granulation, either by dry or wet process, can often be detrimental to the compression properties of materials. Specifically, it is relatively easy to over-granulate if granulation window is not optimized, which leads to significant increase in the median particle diameter and reduction in tabletability.45-47 The additional granulation steps will make the successful implementation of a continuous manufacturing process exponentially more challenging. Thus, other engineering approaches suitable for direct compression to improve flow of pharmaceutical powders are desirable. A number of promising particle and crystal engineering strategies to enhance flow properties of powders are described below. Engineering Strategies to Improve Powder Flow Material Engineering Strategies An effective approach for improving flowability of an API without granulation is to control the crystallization conditions so that larger crystals and crystals with low aspect ratio are obtained. Crystal habit modification for flow improvement can be achieved by using different solvents and by varying other crystallization process parameters, such as solvent addition rate and cooling rate.48-50 It is possible that different solid forms of an API can exhibit different flowability. For example, the flow of citric acid was improved by forming a monohydrate with nearly identical morphology and particle size distributions.51 This is caused by altering the surface structure of the crystals by water of hydration. For APIs that crystallize into the needle-shaped crystals, spherical agglomeration can be an effective strategy to produce API particles with good flow properties.52-55 This process combines crystallization with particle agglomeration to yield particles that are roughly spherical in shape with improved flow behaviors and processability. Spherical agglomeration utilizes specific liquids and polymers to create inter-particulate bridges that generate relatively spherical agglomerates, which enhance the flow properties. Another emerging technology that shows promise to modulate the processability of APIs is microfluidic emulsion-based crystallization platform, which allows the formation of monodisperse spherical particles, providing new material design opportunities to improve
powder flow.56 Finally, controlled nucleation of drug substances on spherical excipient substrates also shows potential to improve the flow properties of poorly flowing APIs.57 Mechanical Dry-Surface Coating With Fine Particles When sophisticated crystallization strategies are not possible or unavailable for controlled crystal size and shape, surface modification of cohesive powders by mechanical dry coating with fine particles can significantly improve flow properties.58,59 This strategy does not change the particle size of the substrate. Its effectiveness originates from the profound reduction of cohesion force among substrate particles by surface coating with fine particles.41 Hamaker's theory shows that the cohesive interaction between adjacent particles (van der Waals interactions) is inversely proportional to the square of their distance of separation.60 This suggests that an increase in the separation between 2 adjacent particles can significantly reduce cohesion, thus improving powder flow. This concept has been successfully demonstrated using various pharmaceutical materials, where dry-surface coating of silica nanoparticles using the dry comilling process significantly improved powder flow.61-65 Avicel PH105 (d50 ~20 micron) is highly cohesive due to the fine particle size distribution. The shear stress applied by the comil led to discretely distributed nano-sized silica particles on the surfaces of Avicel PH105, which significantly improved the flow without significantly reducing the tabletability. While other techniques such as magnetically assisted impaction coating66 and mechanofusion58,67 may also be used to create similar dry nanocoating to enhance powder flow, the attraction of comilling is that it is inherently continuous, thus more suitable for integration in a continuous manufacturing line. Table 2 summarizes the particle and crystal engineering strategies that have been used to enhance powder flow properties of pharmaceutical powders. Figure 1 summarizes the crystal and particle engineering strategies discussed above to improve powder compression and flow properties of pharmaceutical powders.
The Path ForwarddImplementation The concept of materials science tetrahedron depicts the interdependent connection among the structure, properties, processing, and performance of materials.5 Understanding the influence of the structure on the properties of pharmaceutical solids is of particular importance for guiding effective crystal and particle engineering strategies to enable continuous direct compression. In this commentary, we have described some crystal and particle engineering strategies which may be applied to design APIs with robust compression and flow behaviors. The resulting materials are ideally
Table 2 Crystal and Particle and Engineering Strategies to Improve Powder Flow Properties Strategy
Mechanism for Flow Improvement
Impact on Particle Size, Morphology
Impact on Compression
Crystal hydration (e.g., citric acid monohydrate shows better flow than anhydrate1) Combining crystal and particle engineering through spherical crystallization and particle agglomeration Surface modification by dry nanocoating of fine particles by comilling
Alter surface properties of powders to improve flow
Minimal impact on mean particle size distribution or morphology of particles Particle size of spherical agglomerates can be significantly larger than primary particles
Depends on the structure of resultant crystal
Spherical particles, increase in particle size distribution
Increase in interparticulate distance by guest fine particles, reducing cohesive interactions
Minimal increase in mean particle size distribution or morphology of particles
May deteriorate tabletability due to large agglomerate size and less bonding area under compression stress May or may not deteriorate tabletability, depending on the nature of fine particles used for coating and properties of the host powder.
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
5
Figure 1. Integrated crystal and particle engineering strategies to improve powder compression and flow properties for enabling continuous manufacturing by direct compression (DC).
suited for continuous direct compression development, especially when API loading is high. These strategies form the stepping stone toward the implementation of end-to-end continuous pharmaceutical manufacturing by direct compression, where both primary API and secondary drug product processes are integrated. Figure 2 illustrates how the crystal and particle engineering strategies described can be efficiently accommodated to form an end-to-end continuous pharmaceutical manufacturing line that enables direct compression. In this scheme, the API is synthesized continuously through flow chemistry reactors, from which the material will move into the crystallizer. The compression or flow enhancement strategies can either be implemented at this stage in the crystallizer or through subsequent
unit operations, such as dry-particle coating by comilling. The comilling step, if implemented, would also deagglomerate any API particles to further improve flow properties and minimize segregation risks. The engineered API is sufficiently compressible and flowable to allow manufacturing by a direct compression process, where the API will be continuously blended with extragranular excipients, lubricated, compressed, and tablets coated using a continuous coater. The entire cycle with end-to-end continuous manufacturing processing, from API synthesis to completed drug product released in real time, takes much shorter manufacturing time, minimizes costs related to release, shipping, and storage of intermediate materials. This integrated manufacturing system is expected to enhance drug product quality and simplify the control strategy through utilization of
Figure 2. End-to-end continuous pharmaceutical manufacturing with crystal and particle engineering strategies telescoped to enable direct compression. This process is operated in a semicontinuous fashion if any of these unit operations is in batch mode.
6
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
advanced process controls, including PAT and process modeling. It is useful to mention that the implemented crystal and particle engineering strategies for improving powder flowability and tabletability should not compromise other high priority objectives, such as high yield and suitable impurity profile. Conclusions The crystal and particle engineering strategies described in this commentary enable the design of APIs with robust compression and flow properties suitable for continuous tablet manufacturing by direct compression. Their application to enable continuous direct compression process, underpinned by the fundamental understanding of materials science, is an exciting emerging field of pharmaceutical research. The implementation of the end-to-end continuous manufacturing at an industrial scale is currently at an embryonic stage. Our hope is that the particle and crystal engineering strategies described here and future new strategies will eventually enable more widespread adoption of continuous direct compression. Acknowledgment Useful discussions with Philip Dell'orco at GlaxoSmithKline are gratefully acknowledged. References 1. U.S. Food and Drug Administration. FDA report. Final report of pharmaceutical cGMPs for the 21st Centuryea risk-based approach. Silver Spring, MD: FDA; 2004. 2. U.S. Food and Drug Administration. FDA White Paper. Question-based review (QbR) for generic drugs: an enhanced pharmaceutical quality assessment system. Silver Spring, MD: FDA; 2005. 3. U.S. Food and Drug Administration. FDA Report. Implementation of Quality by Design (QbD): Status, Challenges and Next Steps. Silver Spring, MD: FDA; 2006 4. U.S. Food and Drug Administration. FDA Policy & Procedures. Applying ICH Q8(R2), Q9, and Q10 Principles to Chemistry, Manufacturing, and Controls Review. MAPP 5016.1. Silver Spring, MD: FDA; 2016. Available at: https:// www.fda.gov/downloads/AboutFD/UCM242665.pdf. Accessed January 2, 2018. 5. Sun CC. Materials science tetrahedronda useful tool for pharmaceutical research and development. J Pharm Sci. 2009;98(5):1671-1687. 6. Allison G, Cain YT, Cooney C, et al. MIT White Paper on Regulatory and quality considerations for continuous manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium. J Pharm Sci. 2015;104:803-812. 7. Lee SL, O'Connor TF, Yang X, et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J Pharm Innov. 2015;10(3):191-199. 8. Office of Science and Technology Policy, National Science and Technology Council. Advanced manufacturing: a snapshot of priority technology areas across the federal government. Washington, DC: OSTP; 2016. Available at: https://www.whitehouse. gov/sites/whitehouse.gov/files/images/Blog/NSTC%20SAM%20technology%20areas% 20snapshot.pdf. Accessed January 2, 2018. 9. Byrn SR, Futran M, Thomas H, et al. Achieving continuous manufacturing for final dosage formation: challenges and how to meet them. May 20-21, 2014 Continuous Manufacturing Symposium. J Pharm Innov. 2015;104:792-802. 10. Seem TC, Rowson NA, Ingram A, et al. Twin screw granulationda literature review. Powder Technol. 2015;276:89-102. 11. Meng W, Kotamarthy L, Panikar S, et al. Statistical analysis and comparison of a continuous high shear granulator with a twin screw granulator: effect of process parameters on critical granule attributes and granulation mechanisms. Int J Pharm. 2016;513:357-375. 12. Li Z, Zhao L, Lin X, Shen L, Feng Y. Direct compaction: an update of materials, trouble-shooting, and application. Int J Pharm. 2017;529(1):543-556. 13. Ervasti T, Simonaho SP, Ketolainen J, et al. Continuous manufacturing of extended release tablets via powder mixing and direct compression. Int J Pharm. 2015;10(495):290-301. €rvinen MA, Paaso J, Paavola M, et al. Continuous direct tablet compression: 14. Ja effects of impeller rotation rate, total feed rate and drug content on the tablet properties and drug release. Drug Dev Ind Pharm. 2013;39:1802-1808. 15. Jivraj M, Martini LG, Thomson CM. An overview of the different excipients useful for the direct compression of tablets. Pharm Sci Technol Today. 2000;3: 58-63. 16. Li Z, Lin X, Shen L, Hong Y, Feng Y. Composite particles based on particle engineering for direct compaction. Int J Pharm. 2017;519:272-286. 17. Sun CC. Decoding powder tabletability. J Adhes Sci Technol. 2011;25:483-499.
18. Osei-Yeboah F, Chang S-Y, Sun CC. A critical examination of the phenomenon of bonding area - bonding strength interplay in powder tableting. J Pharm Sci. 2016;33(5):1126-1132. 19. Chattoraj S, Shi L, Sun CC. Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1:1 co-crystal. CrystEngComm. 2010;12:2466-2472. 20. Yadav JA, Khomane KS, Modi SR, et al. Correlating single crystal structure, nanomechanical, and bulk compaction behavior of febuxostat polymorphs. Mol Pharm. 2017;14:866-874. 21. Upadhyay P, Khomane KS, Kumar L, Bansal AK. Relationship between crystal structure and mechanical properties of ranitidine hydrochloride polymorphs. CrystEngComm. 2013;15:3959-3964. 22. Weertman J, Weertman JR. Elemental Dislocation Theory. Oxford, UK: Oxford University Press; 1992. 23. Jankovi c B, Joksimovi c T, Stare J, et al. Quantification and modeling of nanomechanical properties of chlorpropamide a, b, and g conformational polymorphs. Eur J Pharm Sci. 2017;110:109-116. 24. Joiris E, Martino PD, Berneron C, Guyot-Hermann A-M, Guyot J-C. Compression behavior of orthorhombic paracetamol. Pharm Res. 1998;15:1122-1130. 25. Sun CC, Grant DJW. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm Res. 2001;18(3):274-280. 26. Reddy CM, Basavoju S, Desiraju GR. Sorting of polymorphs based on mechanical properties. Trimorphs of 6-chloro-2.4-dinitroaniline. Chem Commun. 2005;19:2439-2441. 27. Bag PP, Chen M, Sun CC, Reddy CM. Direct correlation among crystal structure, mechanical behaviour and tabletability in a trimorphic molecular compound. CrystEngComm. 2012;14:3865-3867. 28. Chow SF, Chen M, Shi L, Chow AHL, Sun CC. Simultaneously improving stability, mechanical properties, and dissolution properties of ibuprofen and flurbiprofen by cocrystallization with nicotinamide. Pharm Res. 2012;29: 1854-1865. 29. Chang S-Y, Sun CC. Superior plasticity and tabletability of theophylline monohydrate. Mol Pharm. 2017;14:2047-2055. 30. Sun CC, Hou H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst Growth Des. 2008;8:1575-1579. bia n L, Laity PR, Day GM, Jones W. Improving mechanical 31. Karki S, Fris ci c T, Fa properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Adv Mater. 2009;21:3905-3909. 32. Sanphui P, Mishra MK, Ramamurty U, Desiraju GR. Tuning mechanical properties of pharmaceutical crystals with multicomponent crystals: voriconazole as a case study. Mol Pharm. 2015;12:889-897. 33. Ahmed H, Shimpi MR, Velaga SP. Relationship between mechanical properties and crystal structure in cocrystals and salt of paracetamol. Drug Dev Ind Pharm. 2017;43:89-97. €m€ 34. Mirza S, Miroshnyk I, Heina aki J, et al. Crystal morphology engineering of pharmaceutical solids: tabletting performance enhancement. AAPS PharmSciTech. 2009;10:113-119. 35. Perumalla SR, Shi L, Sun CC. Ionized form of acetaminophen with improved compaction properties. CrystEngComm. 2012;14:2389-2390. 36. Sun CC, Grant DJW. Improved tableting properties of p-hydroxybenzoic acid by water of crystallization: a molecular insight. Pharm Res. 2004;21(2):382-386. 37. Chattoraj S, Shi L, Chen M, Alhalaweh A, Velaga SP, Sun CC. Origin of deteriorated crystal plasticity and compaction properties of 1:1 cocrystal between piroxicam and saccharin. Cryst Growth Des. 2014;14(8):3864-3874. 38. Osei-Yeboah F, Sun CC. Tabletability modulation through surface engineering. J Pharm Sci. 2015;104:2645-2648. 39. Shi L, Sun CC. Transforming powder mechanical properties by core/shell structure: compressible sand. J Pharm Sci. 2010;99:4458-4462. 40. Shi L, Sun CC. Overcoming poor tabletability of pharmaceutical crystals by surface modification. Pharm Res. 2011;28:3248-3255. 41. Kendall K. Adhesion: molecules and mechanics. Science. 1994;263:1720-1725. 42. Geldart D. Types of gas fluidization. Powder Technol. 1973;7(5):285-292. 43. Hou H, Sun CC. Quantifying effects of particulate properties on powder flow properties using a ring shear tester. J Pharm Sci. 2008;97(9):4030-4039. 44. Shi L, Feng Y, Sun CC. Origin of profound changes in powder properties during wetting and nucleation stages of high shear wet granulation. Powder Technol. 2011;208:663-668. 45. Sun CC, Himmelspach MW. Reduced tabletability of roller compacted granules as a result of granule size enlargement. J Pharm Sci. 2006;95(1):200-206. 46. Shi L, Feng Y, Sun CC. Roles of granule size in over-granulation phenomenon during high shear wet granulation. J Pharm Sci. 2010;99:3322-3325. 47. Osei-Yeboah F, Zhang M, Feng Y, Sun CC. A formulation strategy for solving the overgranulation problem in high shear wet granulation. J Pharm Sci. 2014;103: 2434-2440. 48. Banga S, Chawla G, Varandani D, Mehta BR, Bansal AK. Modification of the crystal habit of celecoxib for improved processability. J Pharm Pharmacol. 2007;59(1):29-39. 49. Thakur A, Thipparaboina R, Kumar D, Gouthami KS, Shasstri NR. Crystal engineered albendazole with improved dissolution and material attributes. CrystEngComm. 2016;18:1489-1494. 50. Garekani HA, Sadeghi F, Badiee A, Mostafa SA, Rajabi-Siahboomi AR. Crystal habit modifications of ibuprofen and their physicomechanical characteristics. Drug Dev Ind Pharm. 2001;27(8):803-809. 51. Sun CC. Improving powder flow properties of citric acid by crystal hydration. J Pharm Sci. 2009;98(5):1744-1749.
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7 52. Kawashima Y, Imai M, Takeuchi H, Yamamoto H, Kamiya K, Hino T. Improved flowability and compactibility of spherically agglomerated crystals of ascorbic acid for direct tableting designed by spherical crystallization process. Powder Technol. 2003;130:283-289. 53. Kawashima Y, Okumura M, Takenaka H. Spherical crystallization: direct spherical agglomeration of salicylic acid crystals during crystallization. Science. 1982;216:1127-1128. 54. Kumar S, Chawla G, Bansal AK. Spherical crystallization of mebendazole to improve processability. Pharm Dev Technol. 2008;13:559-568. 55. Katta J, Rasmuson AC. Spherical crystallization of benzoic acid. Int J Pharm. 2008;348:61-69. 56. Leon RA, Badruddoza AZM, Zheng L, et al. Highly selective, kinetically driven polymorphic selection in microfluidic emulsion-based crystallization and formulation. Cryst Growth Des. 2015;15:212-218. 57. Quon JL, Chadwick K, Wood GPF, et al. Templated nucleation of acetaminophen on spherical excipient agglomerates. Langmuir. 2013;29:3292-3300. 58. Qu L, Zhou Q, Gengenbach T, et al. Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate. Drug Dev Ind Pharm. 2015;41:825-837. 59. Zhou Q, Denman JA, Gengenbach T, et al. Characterization of the surface properties of a model pharmaceutical fine powder modified with a pharmaceutical lubricant to improve flow via a mechanical dry coating approach. J Pharm Sci. 2011;100:3421-3430.
7
60. Hamaker HC. The London e van der Waals attraction between spherical particles. Physica. 1937;4:1058-1072. 61. Chattoraj S, Shi L, Sun CC. Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano-silica through comilling. J Pharm Sci. 2011;100:4943-4952. 62. Huang Z, Scicolone JV, Gurumurthy L, Dave R. Flow and bulk density enhancements of pharmaceutical powders using a conical screen mill: a continuous dry coating device. Chem Eng Sci. 2015;125:209-224. 63. Huang Z, Scicolone JV, Han X, Dave R. Improved blend and tablet properties of fine pharmaceutical powders via dry particle coating. Int J Pharm. 2015;478: 447-455. 64. Zhou Q, Shi L, Chattoraj S, Sun CC. Preparation and characterization of surfaceengineered coarse microcrystalline cellulose through dry coating with silica nanoparticles. J Pharm Sci. 2012;101(11):4258-4266. R. Insight into a novel strategy for the design of tablet 65. Capece M, Huang Z, Dave formulations intended for direct compression. J Pharm Sci. 2017;106:1608-1617. 66. Ramlakhan M, Wu CY, Watano S, Dave RN, Pfeffer R. Dry particle coating using magnetically assisted impaction coating: modification of surface properties and optimization of system and operating parameters. Powder Technol. 2000;112:137-148. 67. Zhou Q, Qu L, Gengenbach T, Morton DAV. Investigation of the extent of surface coating via mechanofusion with varying additive levels and the influences on bulk powder flow properties. Int J Pharm. 2011;413:36-43.
Contents lists available at ScienceDirect
Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org
General Commentary
Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression Sayantan Chattoraj 1, *, Changquan Calvin Sun 2, * 1 2
Drug Product Design and Development, GlaxoSmithKline Pharmaceuticals R&D, Collegeville, Pennsylvania 19426 Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, University of Minnesota, Minnesota 55455
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 September 2017 Revised 19 November 2017 Accepted 28 November 2017
Continuous manufacturing of tablets has many advantages, including batch size flexibility, demandadaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process. © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
Keywords: continuous manufacturing direct compression crystal engineering particle engineering formulation design Quality-by-Design compression flow
Introduction The state of pharmaceutical tablet manufacturing is witnessing a strategic shift in the recent years. There is a conscious effort across the pharmaceutical industry to transform the traditional and, somewhat, empirical pharmaceutical development process into a science-based approach that is focused on product quality and process robustness, as stipulated by the Quality-by-Design (QbD) framework.1-3 The paradigm of a QbD filing for regulatory approval of new drug products is no longer a “nice-to-have” for the pharmaceutical industry, as illustrated by the recently published policy from U.S. Food and Drug Administration, MAPP 5016.1, which outlines its expectations for applying International Council on Harmonization ICH Q8(R2), Q9, and Q10 during product development and regulatory review of new drug applications.4 Fundamental to the successful QbD implementation in pharmaceutical
* Correspondence to: Sayantan Chattoraj (Telephone: þ1 610-917-4634; Fax: þ1 610-917-5935) and Changquan Calvin Sun (Telephone: þ1 612-624-3722; Fax: þ1 612-626-2125). E-mail addresses: [email protected] (S. Chattoraj), sunx0053@umn. edu (C.C. Sun).
development is building the understanding of the relationship between the structure and properties of materials as well as manufacturing process relevant to the quality of drug products.5 In addition to embedding the QbD principles, the switch from the traditional batch manufacturing into continuous manufacturing, operated with integrated modelebased controls, is another aspect of pharmaceutical development that is receiving significant attention. Continuous manufacturing is defined as a process where a continuous flow of input raw materials is transformed into finished products under a state of control, with any product manufactured outside the control limits diverted.6,7 Continuous manufacturing of pharmaceuticals has recently been categorized as an advanced manufacturing technology area of emerging priority by the U.S. Federal Government.8 Continuous manufacturing offers a wide spectrum of advantages and has the potential to significantly reduce operational costs and capital costs by: (a) increasing efficiency and shortening development and manufacturing timelines, (b) significantly reducing product losses, (c) reducing operational footprint, (d) increasing consistency of the manufacturing process, and (e) enhancing quality of the product.6,7,9 A true continuous manufacturing line requires every step in the process to be continuous and seamlessly integrated. In many cases,
https://doi.org/10.1016/j.xphs.2017.11.023 0022-3549/© 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
2
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
the design of the continuous line is semicontinuous, having a combination of continuous and batch process steps. Tablet manufacturing by both granulation (wet or dry) and direct compression are amenable to continuous manufacturing. A twin screw granulator or a continuous high shear granulator enables continuous wet granulation.10,11 Continuous dry granulation can be achieved using roller compaction, which is inherently a continuous process. These continuous processes can be integrated with other unit operations to form a continuous manufacturing line. However, direct compression is the most suitable process for continuous manufacturing of pharmaceutical tablets, because of the reduced number of unit operations that need to be integrated for continuous manufacturing. In this case, the input powder blend is directly transformed into a tablet without any intermediate process steps of granulation, drying, and granule size reduction. In addition to the shortened manufacturing time, the reduced number of manufacturing steps, and thus fewer critical process parameters to monitor, ensures process robustness and consistent quality of drug products. Finally, direct compression also eliminates under- or over-granulation problems associated with any granulation process. These advantages have led to a heightened recent interest in the strategies to enable continuous direct compression in both the industry and academia.12-16 The 2 fundamental material properties that impact the manufacturability of tablets are powder tabletability and flowability. The key impediment in the implementation of continuous direct compression is often the sub-optimal compression and flow properties of the active pharmaceutical ingredient (API). The loading of API in a majority of pharmaceutical tablet formulations usually falls in the 10%-80% range depending on the dose. A wider range may be expected if all tablets are considered. At that level, the API compression and flow properties will influence final product manufacturing robustness, especially if the drug loading in the formulation is very high. Therefore, API engineering with the objective of improving the compression and flow characteristics is an effective strategy to enable continuous tablet manufacturing by direct compression, eliminating the need of using significant quantities of excipients to address compression and flow deficiencies of API. The objective of this commentary is to outline API engineering strategies to enhance the powder compression and flow properties of pharmaceutical materials. The current understanding of the fundamental relationships between the structure of materials and their compression and flow properties is summarized. Of course, these engineering strategies are equally applicable to enhance manufacturability during traditional batch processes. Powder Compression The Physics of Powder Compression For a given material, the net mechanical strength of tablets directly depends on the bonding area formed between particles due to permanent particle deformation.17 Tablets would retain integrity only if an adequate area of the interparticulate bonding is preserved after the removal of the compression stress at the conclusion of the compression cycle. The development of bonding area among particles is influenced by particle size, shape, surface texture, moisture content, as well as crystal mechanical properties, which are influenced by crystal structure.17 When the total bonding area is the same, tablets with higher bonding strength are stronger. It is the interplay between bonding area and bonding strength that dictates the tablet compression properties of a powder.18 Thus, particle or crystal engineering for improving bonding area, bonding strength, or both can effectively solve problems related to tablet compression.
To effectively design appropriate crystal and particle engineering strategies for improving the compression properties of an API by influencing bonding area and bonding strength of materials, it is important to understand the fundamental relationships among a material's structure, mechanical deformation, and compression properties.19-21 For a solid material, the key mechanical deformation mechanisms under the application of an external mechanical stress include elastic deformation, plastic deformation, viscoelastic deformation, and fragmentation. Elastically deformed particles undergo complete recovery once the external stress is removed. For perfectly elastic materials, the contact area between particles developed during compression is lost after stress removal. Powders of such materials cannot form intact tablets by compression. For this reason, materials with high elasticity have poor powder compression properties and tend to laminate on decompression due to insufficient bonding area as a result of extensive elastic recovery. Plastic deformation is the most important mechanism for creating a permanent bonding area under compression stress. Irreversible plastic deformation is necessary for retaining the bonding area during the decompression phase of powder compaction and, therefore, for producing robust tablets. Since elastic deformation is inevitable, the compression performance of a powder is largely determined by the relative magnitude of the elastic and plastic deformation. The plasticity of crystals depends on the crystal packing.19,22,23 It has been well documented in the literature that the presence of rigid flat molecular layers in crystals enhances the compression properties of materials by increasing plasticity. These flat layers serve as active slip planes, which are crystallographic planes that have the weakest inter-planar interactions in a crystal. These in turn allow facile movement of dislocations in crystals under mechanical stress, a prerequisite for plastic deformation. A well-known pharmaceutical example of the relationship between crystal structure, plasticity, and powder tabletability is acetaminophen. Acetaminophen polymorph I, having a corrugated herringbone (zig-zag) crystal packing, displays extremely poor powder compression properties. However, acetaminophen polymorph II exhibits flat hydrogen-bonded layers and higher plasticity compared with polymorph I. Consequently, polymorph II exhibits superior compression properties to polymorph I.24 The effectiveness of improving tabletability through enhancing crystal plasticity by introducing flat rigid layered crystal structure is also illustrated in several other polymorphic systems.25-27 Contrary to flat slip layers, a crystal with molecules packed in a 3dimensional hydrogen-bonded network structure exhibit more resistance to plastic deformation, and thereby have poor compression properties.19 When multiple mechanisms of slip are possible in a crystal, crystal plasticity is further improved compared with the simple layered structure. An example of such a material is theophylline, whose crystal structure has flat layers that are formed by stacking hydrogen-bonded V-shaped rigid columns. Slipping between columns is even easier than between rigid layers. In addition, columns between adjacent layers are oriented at an angle of 111.61, thus making them crystal capable of accommodating the compression stress at 2 different orientations to further improve plasticity. This results in exceptional tablet compression properties.19 Other examples of good crystal plasticity and tabletability corresponding to such stacking column structures were also reported.28 Recent work has suggested that ladder-like molecular packing in theophylline monohydrate is responsible for its superior plasticity to theophylline anhydrate.29 Such understanding of the fundamental relationship among the structure, mechanical properties, and tableting behavior at the crystal and tablet levels can now be applied to tailor the compression properties of APIs by crystal and particle engineering.
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
Engineering Strategies to Improve Powder Compression Crystal Engineering Strategies Directing crystallization of an API to a crystal form with structures more amenable to plastic deformation, such as rigid flat layers and layers of stacking columns, can significantly improve the compression properties of otherwise poorly compressible APIs to enable the direct compression process. This strategy, although effective, only has limited application in pharmaceutical development because the choice of a polymorph is often driven by the thermodynamic stability, not by mechanical properties. However, this dilemma can be suitably addressed through forming multicomponent crystals, for example, salts or cocrystals, which allow development of a crystal form exhibiting both suitable mechanical properties and stability.30-33 Structural features that promote tabletability, identified in polymorphic systems, are equally effective in enhancing tabletability of multicomponent crystals. In cases where changing the crystal form is not an option due to the advanced phase of the project in the development lifecycle, other crystal engineering approaches to enhance tablet compression while preserving the crystal form may be needed. Some examples of such approaches include the modification of the crystal habit or morphology to enhance the tabletability,34 and co-processing to balance the material deformation mechanics to achieve optimum tablet compression properties. Table 1 provides illustrative case studies where crystal engineering approaches have been successfully applied to significantly improve the compression properties of pharmaceutical powders. Conversely, any crystal structure modification of APIs that limit plastic deformation by introducing herringbone crystal packing or 3-dimensional hydrogen-boded networks can severely deteriorate the compression properties of pharmaceutical powders.19,37 Also, summarized in Table 1 are the mechanisms by which the compression enhancement is brought about through increased bonding area, bonding strength, or both. Although the accurate quantitation of bonding area and bonding strength is challenging, the qualitative understanding of the relationship among crystal structure, mechanical properties, and tabletability is sufficiently
3
advanced to guide crystal engineering to improve the tabletability of APIs. Our experience is that poor tabletability of API, provided bonding strength is sufficient, is usually solved by increasing crystal plasticity, which leads to a larger bonding area on tablet compression. This implies that bonding strength for most molecular crystals is indeed similar, and at least not significantly different to make enhancing bonding area by improving crystal plasticity ineffective. Particle Engineering Strategies In addition to crystal engineering, particle engineering is another effective strategy to overcome tableting problems of pharmaceutical materials. An effective particle engineering approach to enhance powder compression is surface coating of particles with plastically deforming materials, such as polymers. It has been shown that particle surface coated with plastically deforming materials can render superior tabletability to an otherwise non-compressible elastic powder, as demonstrated with both sand and elastic beads.38,39 For a pharmaceutical example, the elastic polymorph I of acetaminophen had significantly improved tablet compression properties when coated with the plastic polymer hydroxypropyl cellulose.40 Powder Flow The Physics of Powder Flow Another key material property important for ensuring manufacturing robustness of tablets is powder flow. Poor flow of powders is a major concern during pharmaceutical development and scale up because it causes variation in tablet properties as well as poor content uniformity. The physics of powder flow under gravity involves the interplay between 2 universal forcesdinterparticle cohesion, primarily van der Waals forces and gravitational force. While gravity favors powder flow, the attractive cohesive force hinders particle separation that is necessary for powder flow to initiate. Any structural feature that allows gravity to dominate over cohesion favors powder flow. Gravity
Table 1 Illustrative Case Studies of Improving Compression Properties of Pharmaceutical Materials by Crystal Engineering Approaches Crystal Engineering Approach
Illustrative Case Study
Mechanism of Compression Improvement
Reference
Polymorphism
Influence of crystal structure on the tableting properties of sulfamerazine polymorphs: tabletability of polymorph I of sulfamerazine is significantly better than polymorph II. Molecular packing in polymorph I occurs in flat un-corrugated layers, which act as slip planes favoring plastic deformation, while corrugated molecular layers in polymorph II make plastic deformation more difficult Improving compression properties of caffeine by cocrystallization: compression properties of caffeine can be improved by forming cocrystal with methyl gallate. Cocrystallization introduces flat slip layers in the crystal lattice of caffeine-methyl gallate cocrystal Improving compression properties of acetaminophen through formation of hydrochloride salt: Acetaminophen polymorph I shows extremely poor compression. By forming a HCl salt monohydrate of acetaminophen, almost a 200-fold increase in tablet tensile strength is possible Improving compression properties of p-hydroxy benzoic acid by forming monohydrate: the introduction of water in between corrugated layers in the crystal structure of p-hydroxy benzoic acid facilitates plastic deformation resulting in better tabletability of the monohydrate. In addition, the lattice energy of the crystal increases because of the formation of an extensive hydrogen bond network in monohydrate crystal structure
Bonding area enhancement through increasing crystal plasticity by introduction of flat slip planes
25
Bonding area enhancement through increase in plastic deformation by introduction of flat slip planes
30
Bonding area enhancement through increase in plastic deformation by the introduction of flat slip planes
35
Bonding area enhancement through increase in plastic deformation Bonding strength enhancement by increased lattice energy by forming a 3-dimensional hydrogen bonding network
36
Cocrystallization
Salt Formation
Hydrate Formation
4
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
typically can dominate over cohesion for large particles.41 When the particle size is reduced to a critical average particle size of ~30 mm for organic powders, flow issues are often encountered as interparticle cohesion starts to dominate over the gravitational force.42 This is one reason why powder flow of micronized APIs is usually poor. Powder flow is also sensitive to particle shape and surface texture. Generally, more spherical particles flow better than elongated particles43 or particles with smoother surfaces.44 The conventional way to address the flow problem in the pharmaceutical industry is to increase the particle size by granulation. However, granulation, either by dry or wet process, can often be detrimental to the compression properties of materials. Specifically, it is relatively easy to over-granulate if granulation window is not optimized, which leads to significant increase in the median particle diameter and reduction in tabletability.45-47 The additional granulation steps will make the successful implementation of a continuous manufacturing process exponentially more challenging. Thus, other engineering approaches suitable for direct compression to improve flow of pharmaceutical powders are desirable. A number of promising particle and crystal engineering strategies to enhance flow properties of powders are described below. Engineering Strategies to Improve Powder Flow Material Engineering Strategies An effective approach for improving flowability of an API without granulation is to control the crystallization conditions so that larger crystals and crystals with low aspect ratio are obtained. Crystal habit modification for flow improvement can be achieved by using different solvents and by varying other crystallization process parameters, such as solvent addition rate and cooling rate.48-50 It is possible that different solid forms of an API can exhibit different flowability. For example, the flow of citric acid was improved by forming a monohydrate with nearly identical morphology and particle size distributions.51 This is caused by altering the surface structure of the crystals by water of hydration. For APIs that crystallize into the needle-shaped crystals, spherical agglomeration can be an effective strategy to produce API particles with good flow properties.52-55 This process combines crystallization with particle agglomeration to yield particles that are roughly spherical in shape with improved flow behaviors and processability. Spherical agglomeration utilizes specific liquids and polymers to create inter-particulate bridges that generate relatively spherical agglomerates, which enhance the flow properties. Another emerging technology that shows promise to modulate the processability of APIs is microfluidic emulsion-based crystallization platform, which allows the formation of monodisperse spherical particles, providing new material design opportunities to improve
powder flow.56 Finally, controlled nucleation of drug substances on spherical excipient substrates also shows potential to improve the flow properties of poorly flowing APIs.57 Mechanical Dry-Surface Coating With Fine Particles When sophisticated crystallization strategies are not possible or unavailable for controlled crystal size and shape, surface modification of cohesive powders by mechanical dry coating with fine particles can significantly improve flow properties.58,59 This strategy does not change the particle size of the substrate. Its effectiveness originates from the profound reduction of cohesion force among substrate particles by surface coating with fine particles.41 Hamaker's theory shows that the cohesive interaction between adjacent particles (van der Waals interactions) is inversely proportional to the square of their distance of separation.60 This suggests that an increase in the separation between 2 adjacent particles can significantly reduce cohesion, thus improving powder flow. This concept has been successfully demonstrated using various pharmaceutical materials, where dry-surface coating of silica nanoparticles using the dry comilling process significantly improved powder flow.61-65 Avicel PH105 (d50 ~20 micron) is highly cohesive due to the fine particle size distribution. The shear stress applied by the comil led to discretely distributed nano-sized silica particles on the surfaces of Avicel PH105, which significantly improved the flow without significantly reducing the tabletability. While other techniques such as magnetically assisted impaction coating66 and mechanofusion58,67 may also be used to create similar dry nanocoating to enhance powder flow, the attraction of comilling is that it is inherently continuous, thus more suitable for integration in a continuous manufacturing line. Table 2 summarizes the particle and crystal engineering strategies that have been used to enhance powder flow properties of pharmaceutical powders. Figure 1 summarizes the crystal and particle engineering strategies discussed above to improve powder compression and flow properties of pharmaceutical powders.
The Path ForwarddImplementation The concept of materials science tetrahedron depicts the interdependent connection among the structure, properties, processing, and performance of materials.5 Understanding the influence of the structure on the properties of pharmaceutical solids is of particular importance for guiding effective crystal and particle engineering strategies to enable continuous direct compression. In this commentary, we have described some crystal and particle engineering strategies which may be applied to design APIs with robust compression and flow behaviors. The resulting materials are ideally
Table 2 Crystal and Particle and Engineering Strategies to Improve Powder Flow Properties Strategy
Mechanism for Flow Improvement
Impact on Particle Size, Morphology
Impact on Compression
Crystal hydration (e.g., citric acid monohydrate shows better flow than anhydrate1) Combining crystal and particle engineering through spherical crystallization and particle agglomeration Surface modification by dry nanocoating of fine particles by comilling
Alter surface properties of powders to improve flow
Minimal impact on mean particle size distribution or morphology of particles Particle size of spherical agglomerates can be significantly larger than primary particles
Depends on the structure of resultant crystal
Spherical particles, increase in particle size distribution
Increase in interparticulate distance by guest fine particles, reducing cohesive interactions
Minimal increase in mean particle size distribution or morphology of particles
May deteriorate tabletability due to large agglomerate size and less bonding area under compression stress May or may not deteriorate tabletability, depending on the nature of fine particles used for coating and properties of the host powder.
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
5
Figure 1. Integrated crystal and particle engineering strategies to improve powder compression and flow properties for enabling continuous manufacturing by direct compression (DC).
suited for continuous direct compression development, especially when API loading is high. These strategies form the stepping stone toward the implementation of end-to-end continuous pharmaceutical manufacturing by direct compression, where both primary API and secondary drug product processes are integrated. Figure 2 illustrates how the crystal and particle engineering strategies described can be efficiently accommodated to form an end-to-end continuous pharmaceutical manufacturing line that enables direct compression. In this scheme, the API is synthesized continuously through flow chemistry reactors, from which the material will move into the crystallizer. The compression or flow enhancement strategies can either be implemented at this stage in the crystallizer or through subsequent
unit operations, such as dry-particle coating by comilling. The comilling step, if implemented, would also deagglomerate any API particles to further improve flow properties and minimize segregation risks. The engineered API is sufficiently compressible and flowable to allow manufacturing by a direct compression process, where the API will be continuously blended with extragranular excipients, lubricated, compressed, and tablets coated using a continuous coater. The entire cycle with end-to-end continuous manufacturing processing, from API synthesis to completed drug product released in real time, takes much shorter manufacturing time, minimizes costs related to release, shipping, and storage of intermediate materials. This integrated manufacturing system is expected to enhance drug product quality and simplify the control strategy through utilization of
Figure 2. End-to-end continuous pharmaceutical manufacturing with crystal and particle engineering strategies telescoped to enable direct compression. This process is operated in a semicontinuous fashion if any of these unit operations is in batch mode.
6
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7
advanced process controls, including PAT and process modeling. It is useful to mention that the implemented crystal and particle engineering strategies for improving powder flowability and tabletability should not compromise other high priority objectives, such as high yield and suitable impurity profile. Conclusions The crystal and particle engineering strategies described in this commentary enable the design of APIs with robust compression and flow properties suitable for continuous tablet manufacturing by direct compression. Their application to enable continuous direct compression process, underpinned by the fundamental understanding of materials science, is an exciting emerging field of pharmaceutical research. The implementation of the end-to-end continuous manufacturing at an industrial scale is currently at an embryonic stage. Our hope is that the particle and crystal engineering strategies described here and future new strategies will eventually enable more widespread adoption of continuous direct compression. Acknowledgment Useful discussions with Philip Dell'orco at GlaxoSmithKline are gratefully acknowledged. References 1. U.S. Food and Drug Administration. FDA report. Final report of pharmaceutical cGMPs for the 21st Centuryea risk-based approach. Silver Spring, MD: FDA; 2004. 2. U.S. Food and Drug Administration. FDA White Paper. Question-based review (QbR) for generic drugs: an enhanced pharmaceutical quality assessment system. Silver Spring, MD: FDA; 2005. 3. U.S. Food and Drug Administration. FDA Report. Implementation of Quality by Design (QbD): Status, Challenges and Next Steps. Silver Spring, MD: FDA; 2006 4. U.S. Food and Drug Administration. FDA Policy & Procedures. Applying ICH Q8(R2), Q9, and Q10 Principles to Chemistry, Manufacturing, and Controls Review. MAPP 5016.1. Silver Spring, MD: FDA; 2016. Available at: https:// www.fda.gov/downloads/AboutFD/UCM242665.pdf. Accessed January 2, 2018. 5. Sun CC. Materials science tetrahedronda useful tool for pharmaceutical research and development. J Pharm Sci. 2009;98(5):1671-1687. 6. Allison G, Cain YT, Cooney C, et al. MIT White Paper on Regulatory and quality considerations for continuous manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium. J Pharm Sci. 2015;104:803-812. 7. Lee SL, O'Connor TF, Yang X, et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J Pharm Innov. 2015;10(3):191-199. 8. Office of Science and Technology Policy, National Science and Technology Council. Advanced manufacturing: a snapshot of priority technology areas across the federal government. Washington, DC: OSTP; 2016. Available at: https://www.whitehouse. gov/sites/whitehouse.gov/files/images/Blog/NSTC%20SAM%20technology%20areas% 20snapshot.pdf. Accessed January 2, 2018. 9. Byrn SR, Futran M, Thomas H, et al. Achieving continuous manufacturing for final dosage formation: challenges and how to meet them. May 20-21, 2014 Continuous Manufacturing Symposium. J Pharm Innov. 2015;104:792-802. 10. Seem TC, Rowson NA, Ingram A, et al. Twin screw granulationda literature review. Powder Technol. 2015;276:89-102. 11. Meng W, Kotamarthy L, Panikar S, et al. Statistical analysis and comparison of a continuous high shear granulator with a twin screw granulator: effect of process parameters on critical granule attributes and granulation mechanisms. Int J Pharm. 2016;513:357-375. 12. Li Z, Zhao L, Lin X, Shen L, Feng Y. Direct compaction: an update of materials, trouble-shooting, and application. Int J Pharm. 2017;529(1):543-556. 13. Ervasti T, Simonaho SP, Ketolainen J, et al. Continuous manufacturing of extended release tablets via powder mixing and direct compression. Int J Pharm. 2015;10(495):290-301. €rvinen MA, Paaso J, Paavola M, et al. Continuous direct tablet compression: 14. Ja effects of impeller rotation rate, total feed rate and drug content on the tablet properties and drug release. Drug Dev Ind Pharm. 2013;39:1802-1808. 15. Jivraj M, Martini LG, Thomson CM. An overview of the different excipients useful for the direct compression of tablets. Pharm Sci Technol Today. 2000;3: 58-63. 16. Li Z, Lin X, Shen L, Hong Y, Feng Y. Composite particles based on particle engineering for direct compaction. Int J Pharm. 2017;519:272-286. 17. Sun CC. Decoding powder tabletability. J Adhes Sci Technol. 2011;25:483-499.
18. Osei-Yeboah F, Chang S-Y, Sun CC. A critical examination of the phenomenon of bonding area - bonding strength interplay in powder tableting. J Pharm Sci. 2016;33(5):1126-1132. 19. Chattoraj S, Shi L, Sun CC. Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1:1 co-crystal. CrystEngComm. 2010;12:2466-2472. 20. Yadav JA, Khomane KS, Modi SR, et al. Correlating single crystal structure, nanomechanical, and bulk compaction behavior of febuxostat polymorphs. Mol Pharm. 2017;14:866-874. 21. Upadhyay P, Khomane KS, Kumar L, Bansal AK. Relationship between crystal structure and mechanical properties of ranitidine hydrochloride polymorphs. CrystEngComm. 2013;15:3959-3964. 22. Weertman J, Weertman JR. Elemental Dislocation Theory. Oxford, UK: Oxford University Press; 1992. 23. Jankovi c B, Joksimovi c T, Stare J, et al. Quantification and modeling of nanomechanical properties of chlorpropamide a, b, and g conformational polymorphs. Eur J Pharm Sci. 2017;110:109-116. 24. Joiris E, Martino PD, Berneron C, Guyot-Hermann A-M, Guyot J-C. Compression behavior of orthorhombic paracetamol. Pharm Res. 1998;15:1122-1130. 25. Sun CC, Grant DJW. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm Res. 2001;18(3):274-280. 26. Reddy CM, Basavoju S, Desiraju GR. Sorting of polymorphs based on mechanical properties. Trimorphs of 6-chloro-2.4-dinitroaniline. Chem Commun. 2005;19:2439-2441. 27. Bag PP, Chen M, Sun CC, Reddy CM. Direct correlation among crystal structure, mechanical behaviour and tabletability in a trimorphic molecular compound. CrystEngComm. 2012;14:3865-3867. 28. Chow SF, Chen M, Shi L, Chow AHL, Sun CC. Simultaneously improving stability, mechanical properties, and dissolution properties of ibuprofen and flurbiprofen by cocrystallization with nicotinamide. Pharm Res. 2012;29: 1854-1865. 29. Chang S-Y, Sun CC. Superior plasticity and tabletability of theophylline monohydrate. Mol Pharm. 2017;14:2047-2055. 30. Sun CC, Hou H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst Growth Des. 2008;8:1575-1579. bia n L, Laity PR, Day GM, Jones W. Improving mechanical 31. Karki S, Fris ci c T, Fa properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Adv Mater. 2009;21:3905-3909. 32. Sanphui P, Mishra MK, Ramamurty U, Desiraju GR. Tuning mechanical properties of pharmaceutical crystals with multicomponent crystals: voriconazole as a case study. Mol Pharm. 2015;12:889-897. 33. Ahmed H, Shimpi MR, Velaga SP. Relationship between mechanical properties and crystal structure in cocrystals and salt of paracetamol. Drug Dev Ind Pharm. 2017;43:89-97. €m€ 34. Mirza S, Miroshnyk I, Heina aki J, et al. Crystal morphology engineering of pharmaceutical solids: tabletting performance enhancement. AAPS PharmSciTech. 2009;10:113-119. 35. Perumalla SR, Shi L, Sun CC. Ionized form of acetaminophen with improved compaction properties. CrystEngComm. 2012;14:2389-2390. 36. Sun CC, Grant DJW. Improved tableting properties of p-hydroxybenzoic acid by water of crystallization: a molecular insight. Pharm Res. 2004;21(2):382-386. 37. Chattoraj S, Shi L, Chen M, Alhalaweh A, Velaga SP, Sun CC. Origin of deteriorated crystal plasticity and compaction properties of 1:1 cocrystal between piroxicam and saccharin. Cryst Growth Des. 2014;14(8):3864-3874. 38. Osei-Yeboah F, Sun CC. Tabletability modulation through surface engineering. J Pharm Sci. 2015;104:2645-2648. 39. Shi L, Sun CC. Transforming powder mechanical properties by core/shell structure: compressible sand. J Pharm Sci. 2010;99:4458-4462. 40. Shi L, Sun CC. Overcoming poor tabletability of pharmaceutical crystals by surface modification. Pharm Res. 2011;28:3248-3255. 41. Kendall K. Adhesion: molecules and mechanics. Science. 1994;263:1720-1725. 42. Geldart D. Types of gas fluidization. Powder Technol. 1973;7(5):285-292. 43. Hou H, Sun CC. Quantifying effects of particulate properties on powder flow properties using a ring shear tester. J Pharm Sci. 2008;97(9):4030-4039. 44. Shi L, Feng Y, Sun CC. Origin of profound changes in powder properties during wetting and nucleation stages of high shear wet granulation. Powder Technol. 2011;208:663-668. 45. Sun CC, Himmelspach MW. Reduced tabletability of roller compacted granules as a result of granule size enlargement. J Pharm Sci. 2006;95(1):200-206. 46. Shi L, Feng Y, Sun CC. Roles of granule size in over-granulation phenomenon during high shear wet granulation. J Pharm Sci. 2010;99:3322-3325. 47. Osei-Yeboah F, Zhang M, Feng Y, Sun CC. A formulation strategy for solving the overgranulation problem in high shear wet granulation. J Pharm Sci. 2014;103: 2434-2440. 48. Banga S, Chawla G, Varandani D, Mehta BR, Bansal AK. Modification of the crystal habit of celecoxib for improved processability. J Pharm Pharmacol. 2007;59(1):29-39. 49. Thakur A, Thipparaboina R, Kumar D, Gouthami KS, Shasstri NR. Crystal engineered albendazole with improved dissolution and material attributes. CrystEngComm. 2016;18:1489-1494. 50. Garekani HA, Sadeghi F, Badiee A, Mostafa SA, Rajabi-Siahboomi AR. Crystal habit modifications of ibuprofen and their physicomechanical characteristics. Drug Dev Ind Pharm. 2001;27(8):803-809. 51. Sun CC. Improving powder flow properties of citric acid by crystal hydration. J Pharm Sci. 2009;98(5):1744-1749.
S. Chattoraj, C.C. Sun / Journal of Pharmaceutical Sciences xxx (2018) 1-7 52. Kawashima Y, Imai M, Takeuchi H, Yamamoto H, Kamiya K, Hino T. Improved flowability and compactibility of spherically agglomerated crystals of ascorbic acid for direct tableting designed by spherical crystallization process. Powder Technol. 2003;130:283-289. 53. Kawashima Y, Okumura M, Takenaka H. Spherical crystallization: direct spherical agglomeration of salicylic acid crystals during crystallization. Science. 1982;216:1127-1128. 54. Kumar S, Chawla G, Bansal AK. Spherical crystallization of mebendazole to improve processability. Pharm Dev Technol. 2008;13:559-568. 55. Katta J, Rasmuson AC. Spherical crystallization of benzoic acid. Int J Pharm. 2008;348:61-69. 56. Leon RA, Badruddoza AZM, Zheng L, et al. Highly selective, kinetically driven polymorphic selection in microfluidic emulsion-based crystallization and formulation. Cryst Growth Des. 2015;15:212-218. 57. Quon JL, Chadwick K, Wood GPF, et al. Templated nucleation of acetaminophen on spherical excipient agglomerates. Langmuir. 2013;29:3292-3300. 58. Qu L, Zhou Q, Gengenbach T, et al. Investigation of the potential for direct compaction of a fine ibuprofen powder dry-coated with magnesium stearate. Drug Dev Ind Pharm. 2015;41:825-837. 59. Zhou Q, Denman JA, Gengenbach T, et al. Characterization of the surface properties of a model pharmaceutical fine powder modified with a pharmaceutical lubricant to improve flow via a mechanical dry coating approach. J Pharm Sci. 2011;100:3421-3430.
7
60. Hamaker HC. The London e van der Waals attraction between spherical particles. Physica. 1937;4:1058-1072. 61. Chattoraj S, Shi L, Sun CC. Profoundly improving flow properties of a cohesive cellulose powder by surface coating with nano-silica through comilling. J Pharm Sci. 2011;100:4943-4952. 62. Huang Z, Scicolone JV, Gurumurthy L, Dave R. Flow and bulk density enhancements of pharmaceutical powders using a conical screen mill: a continuous dry coating device. Chem Eng Sci. 2015;125:209-224. 63. Huang Z, Scicolone JV, Han X, Dave R. Improved blend and tablet properties of fine pharmaceutical powders via dry particle coating. Int J Pharm. 2015;478: 447-455. 64. Zhou Q, Shi L, Chattoraj S, Sun CC. Preparation and characterization of surfaceengineered coarse microcrystalline cellulose through dry coating with silica nanoparticles. J Pharm Sci. 2012;101(11):4258-4266. R. Insight into a novel strategy for the design of tablet 65. Capece M, Huang Z, Dave formulations intended for direct compression. J Pharm Sci. 2017;106:1608-1617. 66. Ramlakhan M, Wu CY, Watano S, Dave RN, Pfeffer R. Dry particle coating using magnetically assisted impaction coating: modification of surface properties and optimization of system and operating parameters. Powder Technol. 2000;112:137-148. 67. Zhou Q, Qu L, Gengenbach T, Morton DAV. Investigation of the extent of surface coating via mechanofusion with varying additive levels and the influences on bulk powder flow properties. Int J Pharm. 2011;413:36-43.