FORMULATION FORUM - Manufacturing of Solid Oral Dosage Forms by Direct Compression

KEYWORDS: Direct compression, SODF, tableting, co-processed excipients, hardness, compressibility, continuous manufacturing.

INTRODUCTION

Solid oral dosage forms (SODFs) count for more than 80% of marketed drugs, especially for economical and stability reasons, and for easy manufacturing. SODFs can be achieved by several methods. Of those, wet granulation remains a preferred method for achieving the greater compaction and content uniformity, especially for low to medium doses. However, it requires longer drying and processing times as opposed to dry granulation, by roller compaction, and direct compression, which are most preferred and ideal processes with smaller footprints because of their simplicity, yielding greater physico-chemical stability and manufacturing efficiency of moisture sensitive drug products.^1,2

Direct compression (DC) requires blending, mixing, and compression of the ingredients into tablets without going through the wet granulation process that requires milling, drying, screening, and diluting with other ingredients before tableting. Not all excipients are well suited for DC, so challenges remain to find excipients compatible to DC due to certain physicochemical properties associated with poor flowability, lack of plasticity, flexibility, and compressibility. Thus, to enable these excipients with DC properties, additional excipients such as fillers and binders are co-processed to yield highly compressible at low to medium compression forces. The co-processing of two or more excipients may produce new materials with much better properties than individual excipients, making it flexible for greater compressibility with APIs to produce good quality SODFs.³

Poor flowability could stem from fine APIs as well as excipient particulates. These could pose challenges for direct compressibility of the powder blends into tablets. Finer APIs could lead to poor flowability, which could lead to particle segregation and obstacles for achieving higher drug loading. Chen, et al (2019) used spherical crystallization to overcome poor flowability and achieve higher drug loading by using free flowing lactose (Lactose 316).⁴ Spray drying or granulation remains an alternative method for DC by overcoming many other barriers in tableting.⁵

DIRECT COMPRESSION PROCESS

As outlined in Figure 1, the DC process is simpler and more straight forward for making tablets, provided the right criteria for excipients and drug substances are met. The finer grade drug/excipient particulates lead to aggregation, and poor flowability, and hence poor compressibility with increasing drug loading. These can be addressed by wet granulation and/or dry granulation.⁶

The advantages of the DC process include greater chemical stability, APIs less susceptible to hydrolysis or degradation, time-saving and low manufacturing cost, and faster dissolution. The disadvantages of the DC process include higher segregation risk, higher excipient cost (eg, co-processed excipients), fixed composition, and less compactability.

EXCIPIENTS FOR DIRECT COMPRESSION

There are several classes of commonly used dry binders for DC approved in marketed drugs (Table 1).⁷

Citing an example, Margret and Madhavi (2020) evaluated quinapril in DC as the drug is unstable by wet granulation due to moisture. They evaluated a range of excipients to assess the stability of drug at ambient and stressed conditions, and based on the results, lactose monohydrate, crospovidone, and hypromellose were selected for DC.⁸ The powder in pre-blends for DC was characterized by angle for repose, bulk and tapped density, Hausner’s ratio, and moisture content. The content uniformity of drug in compressed tablets was consistent for all three blends, and the dissolution profile was also consistent, showing more than >90% release in 30 min.

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SPRAY DRYING FOR DIRECT COMPRESSION

Spray drying is a unique process for manufacturing composite particles composed of two or more ingredients with poorly soluble APIs dissolved in common organic and/ aqueous solvents. The resulting co-processed composite bulk powder improves the physico-chemical properties, such as flowability, compatibility, and compressibility with respect to individual components used in the composite blend.^9,10 Spray drying excipients without drug is also used to improve the performance of excipients, combined for tableting and the performances of solid oral dosages (SODs). Like many other marketed excipients, Ludipress®, for example, composed of lactose monohydrate, PVP K30, and crospovidone is used as a directly compressible excipient for tableting of drugs (FDA listing). In the following section, we will focus on spray drying of drugs with excipients for yielding DC tablets, which is achieved by particle engineering of morphology to achieve the desired compressibility in high doses with the appropriate excipients, especially those with poor compressible.¹¹

Table 3 shows a number of drugs that can be co-processed in spray dried powder for improved compactability, tabletability, and performance. In the spray drying process, the spray dried droplets coming out of nozzles are affected by atomization and the shear energy applied (inlet and outlet temperatures), which are also dependent on viscosity and surface of the feed solution. In general, high viscosity and surface tension favor larger droplets, on the other hand, high spray energy yields smaller droplets and particulates. APIs sensitive to higher temperatures are most suited because the solvent evaporation in the spray drying process is short, allowing the drug to be less exposed to higher temperatures.

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Chaudhari and Gupte (2017) investigated Avicel HFE with additional 35% mannitol to study the picking and sticking issue of a reference drug (compound XY) by direct compression.¹⁹ It was observed that by blending Prosolv 90 with granular mannitol in reduced amounts improved picking and sticking as opposed to using powder mannitol.

Gohel and Jogani (2005) reviewed co-processed DC excipients. The authors evaluated lactose for improving flowability and compressibility via the freeze-thaw method with PEG6000, povidone, and gelatin at different concentrations and compared the performance with diclofenac sodium as a model drug in Microcelac.⁶ The results were significantly better compared to lactose monohydrate in terms of flowability, compressibility, and disintegration of DC tablets.

One of the major disadvantages of the co-processed excipient mixture is the ratio of each ingredient fixed, and those ratios might not be ideal for the optimal formulation of an API.²⁰ Thus, due to lack of pharmacopeial acceptance, some of the fillers and binders might not be added unless their performance significantly helped improve direct compressibility as opposed to individual components in the physical mixtures. Of several, Kollidon® SR, for example, available as co-processed excipient mixture and composed of polyvinyl acetate and PVP K30 as major components, possesses greater flowability and yields much better hardness on DC as opposed to individual components in the physical mixture.²¹ Kollidon SR is not monographed, but the DC excipients like Compressuc® MS is monographed as Compressible sugar and composed of 96% sucrose with 2.3% maltodextrin and 1.7% inverted sugar. Thus, changing the ratios of the ingredients for better compressibility with higher drug loading might be challenging.

Plasticity remains an important parameter in DC. In comparison with cellulosic excipients, such as microcrystalline cellulose, hydroxypropyl cellulose and povidone K-30, the plasticity of povidone K 30 is about 80% as opposed to about 70% for MCC and HPMC.²² The compression date suggests that Kollidon VA 64 (copovidone) is not adversely affected by increasing the compression pressure at 18 kN and 25 kN, while the cellulosic excipients showed far less compressible in DC at 18 kN and 25 kN. Thus, Kollidon VA 64 plasticity can be used as a marker for higher drug loading of crystalline drugs in direct tableting. For example, ascorbic acid, when directly compressed in crystal and powder with 5% Kollidon VA64, showed the hardness of about 95 N and 130 N, respectively. In another example, highly crystalline acetylsalicylic acid powder (400 mg) when compressed in 516 mg tablet comprised of co-processed Ludipress® (99 mg) with Kollidon CL (15 mg) and stearic acid (1 mg), yielded the hardness of 90 N with friability of <0.4% and >97% dissolution in 30 min. The tablets were stable over 12 months at ambient and accelerated conditions showing less than 0.2% salicylic acid formation.²²

Ludiflash® – a co-processed directly compressible excipient composed of mannitol, crospovidone, and polyvinyl acetate has been evaluated in orally dispersive tablets. The flowability of Ludiflash with fine particle APIs could lead to particle segregation. In such cases, the addition of 1%-3% colloidal silica improves the flowability in direct compression.²³

Kollitab® DC 87 L, a DC-grade excipient composed of 84.5%-88.5% Lactose monohydrate, 8%-10% crospovidone (Kollidon CL-SF), 3%-4% PEG-PVA-copolymer (Kollicoat IR) and 0.8%-1.8% sodium stearyl fumarate, a co-processed excipient prepared by spray-drying.²⁴ In DC with 25% acetylsalicylic acid, Kollitab gives harder tablet with tensile strength of >2 MPa at compression of 200 MPa or higher, suggesting it can be used for high drug loading without compromising the hardness and dissolution properties of the tablets. It is also true with vardenafil HCl tablets comprised of 2% to 8% drug loading with yielding the hardness of >90 N at compression force of 9 kN for 2% drug and 6 kN for 8% drug.

Kollicoat Protect, a co-processed moisture barrier coating polymer, composed of 60% Kollicoat IR and 40% polyvinyl alcohol, was investigated as directly compressible binder with crystalline drugs. In comparison with its parent polymer Kollicoat IR, the hardness of Kollicoat Protect tablets continuously increased with increasing compression force to 6-fold, whereas for Kollicoat IR tablets hardness unchanged (3-4 kP) as the compression force increased to 22 kN.²⁵

Other examples include Emedex®, which is a directly compressible grade excipient co-processed with 95% glucose monohydrate and different oligosaccharides from starch (NF, Dextrates) and on compression with 25% highly crystalline ascorbic acid, yields harder tablets with 70 N hardness as compared to DC-grade sorbitol, isomalt, and granulated lactose.²⁶

While spray granulation or drying of the excipients in a co-processed mixture or drug with and without excipients is widely used for preparation of directly compressible dry binders, Chen et al (2019) used a quasi-emulsion solvent diffusion (QESD) method for crystal engineering of a model drug ferulic acid (FA) aimed at attaining bulk crystal powder to achieve high drug loading in a DC tablet.4 The tablets derived from QESD with <1% HPMC met the criteria for tablet design but; however, the disintegration time was >30 min, which is longer than the required 15 min or less for an immediate tablet. To further improve the disintegration time to <10 min, and the ejection force to <400 N, 0.75% crospovidone and 0.25% magnesium stearate were added. Upon compression, QESD with 99% FA loading showed an excellent compressibility and met all the criteria for flowability, friability, tabletability, and dissolution. In comparison with MCC PH 102, QESD showed over 6-fold higher flowability.

FUTURE PERSPECTIVES & SUMMARY

As more new molecules continue to be discovered, so is the increase in number of innovative co-processed excipients for development of directly compressible tablets. In the past decade, excipient manufacturers have taken steps to launch new co-processed excipients with the interest to use in continuous manufacturing and also to improve the processing time to reduce footprint and lower the cost. DC of co-processed excipient mixture is normally accepted as the best choice for poorly compressible drugs with sluggish flowability and compactability into tablets. Particle engineering by granulation or solvent diffusion, spherical agglomeration, and crystallo-co-agglomeration is often used for improving flowability of crystalline drugs without impacting the physico-chemical properties in DC tablets with high loading.

As continuous manufacturing (CM) comes at the heels of drug manufacturing to reduce cost and to lower the risk of material hold-ups, the industry is moving toward continuous direct compression (cDC) to improve homogeneity with higher yield and greater flexibility to eliminate the traditional steps like granulation, drying, and sieving before tableting or filling in two-piece hard gel capsules.^27-29 Ascendia with its expertise and cGMP manufacturing capabilities with ISO cleanrooms in injectable and oral liquids and SODFs can lead the way in expediting the formulation development of innovative molecules to the clinic faster. Our enabling technologies, AmorSol®, NanoSol®, EmulSol®, and LipidSol™ are aimed at addressing the challenges with poorly soluble drugs in oral and parenteral formulations.

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Dr. Shaukat Ali joins Ascendia Pharmaceutical Solutions as Senior Director of Scientific Affairs and Technical Marketing after having worked in the pharma industry for many years. His areas of expertise include lipid chemistry, liposomes, lipid nanoparticles, surfactant-based drug delivery systems, SEDDS/SMEDDS, oral and parenteral, topical and transdermal drug delivery, immediate- and controlled-release formulations. He earned his PhD in Organic Chemistry from the City University of New York and carried out his post-doctoral research in Physical Biochemistry at the University of Minnesota and Cornell University. He has published extensively in scientific journals and is inventor/co-inventor of several US and European patents.

Dr. Jim Huang is the Founder and CEO of Ascendia Pharmaceutical Solutions. He earned his PhD in Pharmaceutics from the University of the Sciences in Philadelphia (formerly Philadelphia College of Pharmacy and Sciences) under Joseph B. Schwartz. He has more than 20 years of pharmaceutical experience in preclinical and clinical formulation development, manufacturing, and commercialization of oral and parenteral dosage forms. His research interests are centered on solubility/bioavailability improvement and controlled delivery of poorly water-soluble drugs through nano-based technologies.