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Excipients Vinay Muley, Fernanda Onofre, Michael Baumann, and Juergen Engelhardt Dupont Nutrition & Biosciences

Excipients Vinay Muley, Fernanda Onofre, Michael Baumann, and Juergen Engelhardt Dupont Nutrition & Biosciences

eyeAs appeared in May 2020 Tablets & Capsules Copyright CSC Publishing www.tabletscapsules.com on excipients Vinay Muley, Fernanda Onofre, Michael Baumann, and Juergen Engelhardt DuPont Nutrition & Biosciences

Manufacturers favor continuous direct making it more economical than tra- ing, may be the answer. They offer compression of formulations ditional batch tableting. functionalities exceeding those of because it is economical and efficient, but While direct compression of a traditional physical excipient blends, formulation improves efficiency, the allowing formulators to reduce man- the process presents a variety of manu- lack of an intermediate granulation ufacturing steps while ensuring tablet facturing challenges related to content step can present a challenge because quality. Co-processed excipients lend uniformity, compactibility, and flow. most pharmaceutical ingredients do themselves well to continuous opera- This edition of “Eye on Excipients” not have inherent binding proper- tions because they are engineered to explores a method for incorporating a ties. High-dose tablets may lack suf- achieve the synergistic properties of ficient tensile strength if the active a tableting blend’s key components co-processed excipient into a tablet for- pharmaceutical ingredient (API) is in a single, highly flowable and com- mulation to facilitate direct compression not easily compressible, while low- pressible [2]. tableting and create more robust tablets. dose formulations may be difficult Formulators whose DC tablet- to blend uniformly. Additionally, ing operations are faced with par- Although traditional batch pro- since some APIs are hygroscopic ticle segregation, poor API content cessing has long been the norm in and thermolabile (heat sensitive) in uniformity, and excipients plugging the pharmaceutical industry, nature, they can be difficult to com- or blocking the manufacturing pro- product manufacturers have begun press. Excipients, such as diluents, cess should seek out an excipient that to shift toward continuous manufac- fillers, and binders can play a signif- improves flow and tablet turing as a more sustainable, eco- icant role in improving a formula- compactibility, thus helping to main- nomical, and time-efficient method. tion’s content uniformity, flow, and tain API uniformity within the tablets. Key benefits of continuous manu- compaction properties as well as the This article describes a study in facturing include better process con- resulting tablet’s tensile strength. which researchers, using different trol, simpler scale-up or none at all, grades of a co-processed excipient, enhanced safety margins, increased Incorporating co-processed examined powder flow, compact- productivity, and improved quality excipients ibility, and tablet tensile strength, and yields. In addition, the equip- One of the keys to overcoming during the direct compression pro- ment needed for continuous man- these challenges is to select excip- cess. For the study, the researchers ufacturing is much smaller than its ients that both integrate well with selected a silicified microcrystalline batch counterpart, and it operates at the formulation and offer suitable (Avicel SMCC, DuPont) a steady state, which facilitates auto- powder flow properties, to ensure that consists of 98 percent w/w mation and process monitoring. consistent tablet weight and content microcrystalline cellulose (MCC) Tablets are the most common uniformity. Choosing the correct and 2 percent w/w . , comprising around 70 excipient can also help manufacturers They chose SMCC because it does percent of the global oral drug deliv- avoid ingredient segregation during not alter the chemical structure of ery market [1]. As a result, many for- the blending process, improve flow MCC yet exhibits improved compac- mulators transitioning to continuous and transfer to the equipment train, tion and powder flow properties. operations have led with direct com- and achieve proper lubrication for The researchers first examined the pression (DC) tableting. Continuous one-step mixing. flow characterization of the SMCC DC tableting allows for the ingredi- Co-processed excipients, which according to the pharmacopoeial ents to be processed and compressed are a combination of two to three methods [3], and performed a vari- seamlessly without a granulation step, excipients developed via co-process- ety of simple and rapid tests, such as Copyright CSC Publishing Figure 1 Figure 2 Figure 3 Angle of repose for different Carr’s compressibility FT4 powder rheometer SMCC grades versus MCC index for different SMCC flow-test data for different grades versus MCC SMCC grades versus MCC

40 36.0 36 35 32.6 33 33 29.7 30.1 32 26.9 26.7 Above FFC 10 23.2 21.5 indicates free flowing 17.9

Angle of repose 6.6 7.5 101 102 302 50 90 HD 90 101 102 302 50 90 HD 90 Flowability (FFC)

Compressibility index 101 102 302 50 90 HD 90 MCC SMCC MCC SMCC MCC SMCC Material type and grade Material type and grade Material type and grade angle of repose, Carr’s compressibility The researchers measured the will be closer to each other than in a index, and powder density (bulk and angle of repose in degrees, with an poorly flowing powder. tapped). In addition, they conducted angle greater than 66 degrees indi- Using the bulk and tapped density advanced flow tests using a pow- cating “very, very poor” flowabil- values, the researchers determined der rheometer (FT4, Freeman) and ity and 25-30 degrees indicating the Carr’s compressibility index and ring shear tests, as well as scanning “excellent” flowability. As Figure 1 Hausner ratio for each material. A electron microscopy (SEM) to char- indicates, the SMCC grades demon- compressibility index value greater acterize the excipient’s powder mor- strated increased flowability com- than 38 percent is considered “poor,” phology. The researchers then used pared to the MCC grades. while 16 to 20 percent is considered a compaction simulator—an instru- The researchers then measured the “excellent.” As Figure 2 indicates, mented single-punch hydraulic tab- materials’ bulk and tapped densities the SMCC grades demonstrated let press that simulates the operation using a bulk and tap density apparatus increased flowability compared to of a rotary tablet press—to explore (Electrolab, India) and compared the the MCC grades. whether the co-processed excipient values. Tapped density is a material’s The flow-test data (Figure 3) and can help to formulate more-robust bulk density after mechanical tapping ring-shear-test data (Figure 4) also tablets in direct compression than the of a sample in a graduated measuring indicate that SMCC is a free-flowing traditional excipient (Avicel MCC, cylinder. In a free-flowing powder, material that allows for tablets with DuPont). there is less interparticle , so excellent weight and content unifor- the bulk and tapped density values Powder flow tests The researchers used a powder flow tester for the angle of repose Figure 4 test, a characteristic test to deter- Ring-shear-test data for different SMCC grades mine interparticle friction based on the three-dimensional angle made Non flowing Very cohesive Cohesive Easy flowing by a cone-like pile of material. For 4,000 the procedure, researchers used a Avicel SMCC 50 100-millimeter-diameter base plate 3,500 Avicel SMCC 90 and fixed a funnel 40 millimeters Avicel SMCC HD90 above the plate, allowing the powder 3,000 to fall on the base plate through a 10-millimeter funnel orifice, without 2,500 any vibration to the funnel or base. 2,000 The quantity of powder was sufficient to form a cone, with the excess falling 1,500 over the edge of the base plate. The height of the cone was mea- 1,000 sured with a calibrated digital Vernier, and the angle of repose was calculated Unconfined yield strength (pascals) 500 with the following formula: Free flowing 0 tan (a) = height (0.5 base) 0 5,000 10,000 15,000 20,000 Maximum principle stress (pascals) Copyright CSC Publishing mity, attributes that can be difficult to achieve in DC processes. Figure 5 tablet tensile strength at different compression Tablet compaction tests pressures (higher slope indicates better compactibility) The tablet compaction cycle has three different stages that determine 7.0 the tablets’ mechanical and physi- cochemical characteristics: pre-com- 6.0 Slope: 0.078 pression, main compression, and ejection. Using the compaction sim- 5.0 ulator (ESH, UK) the researchers Slope: 0.076 focused on measuring all the param- 4.0 eters of the compaction cycle. They Slope: 0.054 then evaluated the material character- 3.0 istics by correlating and computing parameters, along with finished tablet 2.0 properties such as weight variation, Avicel SMCC 50 Avicel SMCC 90 hardness, thickness, and diameter. Tensile strength (megapascals) 1.0 Avicel SMCC HD90 For the compaction trials, the researchers fitted the compaction 0.0 simulator with 13-millimeter-diame- 20 40 60 80 100 ter, flat-face punches and compacted Compression pressure (megapascals) about 500 milligrams of powder into tablets. The contact time, a general indicator of compaction speed, was suitable for DC tableting and con- The overall surface examination and 0.028 seconds. To vary the maxi- tinuous manufacturing processes the flow studies of SMCC provides mum compression pressures, the than traditional MCC. important morphological informa- researchers kept the upper punch dis- In addition, the surface morpho- tion about the improvement in the placement profiles as sine waves with logical studies of the SMCC (Figure functional characteristics and parti- different amplitudes. They followed 6) show uniform distribution of col- cle surface modifications. pre-lubrication with magnesium stea- loidal silicon dioxide particles over rate, to avoid frictional damage of the surface of the MCC particles, Conclusion the punch and die set. which is essential for the excipi- The study shows that SMCC’s Researchers then packed the pre- ent’s improved functional character- properties extend beyond the tradi- pared tablets into HDPE bottles, istics. To some extent, deposition tional MCC excipient capabilities, with a separate bottle for each dif- was also observed in the inter-spa- with improved binding and advanced ferent compression force, and stored tial structure of the MCC particles. physical and morphological proper- the bottles in a desiccator with con- ties. In addition, this demonstrates trolled humidity for complete phys- ical relaxation. After 24 hours of Figure 6 storage, they analyzed the tablets for SEM image of SMCC (white spots indicate homogeneous weight variation, hardness, thickness, distribution of silicon dioxide over the MCC particle) and diameter and then calculated the compaction slope value and tablet tensile strength based on the hard- ness and compaction force data. During the compaction process, the tablet tensile strength increases proportionally with the compaction pressure. The specific increase of the tensile strength (as indicated by the slope of the curve in Figure 5) is higher for the SMCC grades than for the MCC. As Figures 1 through 5 show, the co-processed SMCC excipient exhibits excellent flow and com- paction properties, making it more Copyright CSC Publishing that a co-processed excipient such 6. Mira Jivraj, Luigi G. Martini, as SMCC lends itself to improved and Carol M. Thomson, “An over- flow and better compactibility during view of the different excipients useful compression, which results in lower for the direct compression of tab- tablet weight variation and better lets,” Pharmaceutical Science & Technology content uniformity. These traits allow Today, 2000, Vol. 3, No. 2, pages formulators to produce a robust tablet 58-63. as well as facilitate DC or alternative continuous manufacturing processes. Michael Baumann is global strategic As the trend toward continuous marketing manager, immediate-release pharma manufacturing continues, it is essential that manufacturers are pharmaceutical dosage forms; Vinay equipped with excipients that are Muley is India leader, technology & optimized for such operations, since innovation, pharmaceutical solutions; incorporating the incorrect excipient Fernanda Onofre is Americas regional can cause a manufacturing process applications leader, pharmaceutical to malfunction. This study shows that co-processed excipients, such as solutions; and Juergen Engelhardt is SMCC, can help solve many con- technical fellow, pharmaceutical solu- tinuous manufacturing challenges by tions, at DuPont Nutrition & Biosci- improving flow, compactibility, and ences. For questions or comments about tablet tensile strength. Formulators this article, please contact Lindsay Tor- should consider that these attributes may make co-processed excipients riero, global communications leader, such as SMCC beneficial in pro- pharmaceutical solutions, DuPont cesses besides DC tableting as well, Nutrition & Biosciences (lindsay.torri such as multi-particulate systems or [email protected]). dry granulation. T&C

References 1. Purushottam R. Patil, Vaibhav D. Bobade, Pankaj L. Sawant, and Rajendra P. Marathe, “Emerging trends in compression coated tablet dosage forms: A review,” International Journal of Pharmaceutical Sciences and Research, March 2016. 2. “Excipients in Pharmaceuticals,” BCC Research, March 2016. 3. Chapter 1174, Powder Flow, USP-NF. 4. B. van Veen, G.K. Bolhuis, Y.S. Wu, K. Zuurman, and H.W. Frijlink, “Compaction mechanism and tablet strength of unlubricated and lubri- cated (silicified) microcrystalline cel- lulose,” European Journal of Pharmaceutics and Biopharmaceutics, 2005, Vol. 59, No. 1, pages 133-8. 5. Stephen Edge, Ursula J. Potter, D. Fraser Steele, Michael J. Tobyn, Ansong Chen, and John N. Staniforth, “The location of silicon dioxide in silicified microcrystalline cellulose,” Pharmacy and Communications, 1999, Vol. 5, No. 6, pages 371-6.