Issue link: https://www.e-digitaleditions.com/i/922724
12 January 2018 Tablets & Capsules From the beginning The benefits of hard capsules start in R&D, where they enable manufacturers to reduce a drug product's time-to- market. During product development, capsules are simple to handle on a small scale and can be filled manually or with semi-automatic equipment that is comparable to industrial-scale capsule fillers in terms of compression force. The filled capsules also perform comparably in dis- solution testing. Furthermore, they are more suitable for use when the API is in short supply because they con- serve costly material. Hard capsules also facilitate proof- of-concept exercises, possibly eliminating the need to formulate because neat API can be dosed to the capsule. This absence of formulation involves minimal risk of incompatibility regarding API stability because the only possible interaction would be with the capsule shell. As an investigational drug product moves toward pre-clinical and toxicity testing, tiny hard capsules enable researchers to deliver the correct dose to the stomach of conscious animals without stressing them. When advanc- ing to clinical testing with humans, the usual choices include chemical-in-capsule, formulated capsules (includ- ing binary blends), and chemical-in-capsule-in-bottle. Which to use depends on whether an exploratory or commercial approach is selected. Exploratory formulation approach. This option calls for the simplest possible formulation applicable to clinical testing (such as neat API-in-capsule). The goal is to achieve early-phase safety and proof-of-concept data. Commercial approach. Here the objective is to pro- duce a formulation that resembles the commercial formu- lation, usually involving second-generation compounds. This approach can reduce the need for bioequivalence studies in later stages of clinical testing. Whatever the strategy, hard capsules offer a high degree of flexibility in Phase I formulations because they enable you to cover a wide range of doses in the trial, such as 1, 10, and 100 milligrams. In addition, the variety of colors and sizes of capsules makes them well suited for preliminary drug studies and blinded clinical trials. Clinical trials In the past, clinical trials typically used hard capsules for preliminary development, followed by a tablet formulation when the scale of the trials increased. Although this gener- ally was considered an easy conversion, the regulatory requirements have changed in the last 25 years. Changing the dosage form requires robust evidence, including stabil- ity studies (ICH Q1), in vitro bioequivalence studies for drug products of all BCS classes, and possibly in vivo test- ing (particularly for BCS classes II and IV), which is quite expensive. Switching from a capsule to a tablet at the end of Phase II clinical trials, however, is still common because many pharmaceutical production sites have tablet presses that are qualified and ready to use. Another point to con- sider is that the sites have staff skilled in tabletting and the GMP certifications, validations, and documentation required to make tabletted drug products. Manufacturing advantages However, in the realm of SODFs drug products, capsules retain several advantages over tablets: Capsules often require fewer excipients than tablets. In addition to the active(s), both dosage forms typically include diluent(s) and a lubricant. Capsule formulations, however, may only require adding a glidant, while tablets require, at minimum, a disintegrant and a binder if they are dry- or wet-granulated. Coated tablets incorporate even more excipients. See Table 1. Capsules require less compression force than tablets. The force applied to form a powder plug to fill the cap- sule ranges between 0.01 and 0.1 kilonewtons, while tab- lets are compressed at 10 to 100 kilonewtons. Manufacturing speed facilitates scale-up. An average tablet press operates faster than most capsule fillers, but the speed of plug formation in capsule filling is the same for both low- and high-speed capsule fillers. This is not true of tablet presses, and a tablet formulation designed using a low-speed press may not perform the same when it moves to a high-speed machine. Table 1 Number of excipients included in tablet and capsule formulations Number of excipients Tablet product Coated tablet product Capsule product 1 to 2 • Metamizol • Ultibro Breezhaler (indacaterol and gylcopyrro- nium bromide) • Tranxilium (dipotassium clorazepate) • Clamoxyl (amoxicilin) 3 to 5 • Aciclostad (aciclovir) • Acentensil (enalapril) • Eutirox (levotiroxina) • Primperan (metoclopramide) • Clamoxyl (amoxicilin) • Lyrica (pregabalin) • Celebrex (celecoxib) • Enantyum (dexketoprofen) • Fluconazol • Tacrolimus 6 to 9 • Paracetamol • Acfol (folic acid) • Dilitiazem • Losartan • Crestor (rosuvastatina) • Zomig (zolmitriptan) • Enantyum (dexketoprofen) • Ebastel (ebastin) • Brainal (nimodipin) • Sertralina More than 9 • Tryptizol (amitriptyline) • Aldomet (methyldopa) • Atripla (efavirenz, emtricitabina, and tenofovir disoproxil) • Levonorgestreland ethinyl estradiol • Omeprazol