Research Article Investigating the Effect of APAP Crystals on Tablet Behavior Manufactured by Direct Compression Nastaran Ghazi, 1,2,4 Zhanjie Liu, 2,3 Chinmay Bhatt, 2,3 San Kiang, 2,3 and Alberto Cuitino 1,2 Received 5 December 2018; accepted 19 March 2019 Abstract. In this work, the effect of API’s (Active Pharmaceutical Ingredient) shape and size on tablet characteristics is investigated for high API dose formulation manufactured by direct compression. Three different classes of APAP (acetaminophen) are selected, and tablets are produced in both single and batch processes. After performing and comparing comprehensive series of standard characterization tests including hardness, dissolution, disintegration, and friability on the tablets, the test results show the relation between the quality of APAP tablets and the shape and size of the crystals. We also investigate the effect of scaling up the manufacturing process (from single to batch) by evaluating dosage uniformity and possibility of segregation in blends. The results indicate a strong interaction between manufacturing parameters such as speed and scale of production to API crystal size and shape. This places crystal properties in the critical parameter set that requires tracking and monitoring in order to maintain consistent tablet properties in high-dose formulation continuous manufacturing operations. KEY WORDS: APAP; direct compression; high-dose API; API crystals; tablet properties. INTRODUCTION Tablets consist of the majority of oral solid dosage forms among various pharmaceutical products. Their popularity is mainly because of their low cost and simplicity of manufactur- ing, convenience of dosing to patients, flexible dissolution profile, and high stability. There exist several manufacturing strategies to manufacture tablets including dose utilizing wet granulation, dry granulation, and direct compression. The simplest and most desirable one is, however, direct compres- sion (DC) (1). This method requires a minimal number of operational steps, typically feeding and blending followed by tableting (2). Significant challenges in direct compression arises when compacting high-dose APIs (Active Pharmaceutical Ingredi- ents) that generally exhibit low flowability and poor com- pressibility (3–6). In addition, some APIs such as APAP (acetaminophen) show significant elastic deformation during compaction process which is leading to a high tendency to capping even at low doses (7). There are numerous works on seeking different routes to mitigate the above challenges including formulation design (selecting materials) and/or manufacturing design (selecting process steps/variables). In the formulation de- sign, compaction of the blend properties are improved by choosing the optimized set of components (excipient, lubricant, disintegrants, etc.)(8,9); while in the manufactur- ing design, it is done by modifying crystallization process (primary manufacturing), or sieving, milling, or granulation (secondary manufacturing) in order to change crystal habit (shape, size, or surface area) or morphology (internal structure) (10–12). In particular, changing crystal habits for different APIs has been shown to directly affect the physicochemical properties of tablet leading to change in flowability and compaction properties (13–16). There are also several works, which specifically focus on different approaches to engineering the crystallization process of APAP to change its morphology and habit or add coating to the crystals and discuss its role on tablet quality. These works generally show the results on directly compacted APAP with no or only one excipient (17–19) and in few cases for APAP in formulation blends (20–22). However, in each of the works mentioned above, the quality of APAP tablets is only measured based on a few characterization tests such as the compaction behavior, hardness or flowability, and dissolution (17,18,20–22). Therefore, the lack for a complete work on tablets based on the crystal habit that covers all characteristic aspects of the product is felt. 1 Department of Mechanical and Aerospace Engineering, Rutgers University, 98 Brett Road, Piscataway, New Jersey 08854, USA. 2 Center for structured organic particulate systems, Rutgers Univer- sity, New Brunswick, New Jersey, USA. 3 Department of Chemical and Biochemical Engineering, Rutgers University, New Brunswick, New Jersey, USA. 4 To whom correspondence should be addressed. (e–mail: Nastaran.ghazi@gmail.com) AAPS PharmSciTech (2019) 20:168 DOI: 10.1208/s12249-019-1369-0 1530-9932/19/0000-0001/0 # 2019 American Association of Pharmaceutical Scientists