Federica Giatti, Massimo Malavolti, Fabriano Ferrini, and Caterina Funaro, IMA Active
A minitablet is generally a round tablet with a flat or slightly convex face and a diameter between 1.0 and 3.0 millimeters. Minitablets are usually filled into a capsule, but they are also occasionally compressed into larger tablets or placed in sachets for easy administration.
Minitablets combine the advantages of multiparticulate dosage forms with the established manufacturing techniques of tableting. Their small size gives them several advantages over traditional single-unit dosage forms, including being easier to swallow for geriatric and pediatric patients, who tend to experience difficulty swallowing large tablets or capsules.
Minitablets usually provide a more reliable in vivo dissolution performance and a higher degree of dispersion in the gastrointestinal (GI) tract than single-unit dosage forms. This can result in more consistent dose-to-dose bioavailability and clinical effect, with a lower risk of dose dumping.
Minitablet production has fewer constraints than extrusion and spheronization, which is used to create multiparticulate pellets. When manufactured using direct compression (DC) (as opposed to granulation or extrusion and spheronization), minitablet production is a single step, which can result in low manufacturing costs and high production yields. Additionally, DC tableting does not require the use of liquids, which makes minitablets an attractive alternative to pellets.
Minitablets can be also coated and combined to achieve various drug release profiles within a single dosage form, allowing for easier and more successful treatment of diseases that require a multi-target therapy approach.
Film coating minitablets As with traditional tablets, film coating of minitablets provides several advantages, including:
- masking unpleasant tastes or odors;
- improving swallowability;
- helping to positively impact patient preference;
- differentiating the product’s visual appearance to minimize dispensing errors;
- improving packaging efficiency;
- preventing cross contamination; and
- reducing tablet breakage and chipping during manufacture.
Most pharmaceutical drug substances have a moderately to highly unpleasant taste that can range from a lingering chemical taste to harsh bitterness. As a result, taste masking has become a necessary process step for many drug products, and manufacturers have developed different technical approaches for various dosage forms and drug substances. Taste masking is particularly important for patient adherence in the pediatric field, especially if the taste-masking polymer also eases the product’s swallowability.
Until recently, manufacturers have primarily used fluid-bed processes rather than drum coaters to taste mask minitablets. However, drum coating can have several advantages over fluid-bed coating, including higher production capabilities, reduced coating-material waste, and faster equipment cleanup. Drum coating of minitablets is usually performed using a solid drum, but a perforated drum increases the air volume moving through the machine and can improve performance.
The following study evaluates a minitablet production process, including compression in a rotary tablet press, formulation of a taste-masking coating, and coating application feasibility in pilot- and production-scale drum coaters with a perforated drum type specifically designed for multiparticulate oral solid dosage forms.
Minitablet production and testing
For the study, researchers produced 2.5-millimeter diameter placebo minitablets on an IMA Prexima 300 rotary tablet press. The tablet press used a standard feeder system equipped with flat paddles rotating at 40 rpm. The placebo formulation was supplied by Meggle and contained lactose monohydrate, cellulose, aluminum oxide, and magnesium stearate as lubricant.
The minitablets were compressed at 7 kilonewtons main compression force and tested for uniformity of mass, friability (Roche friabilator), and crushing strength (Erweka), and their surface characteristics were observed by scanning electron microscopy (FEI ESEM Quanta 200). The tableting process yielded smooth, stable minitablets that weighed 13 milligrams and had a hardness of 30 newtons and a friability below 0.1 percent—ideal characteristics for coating.
Achieving this level of quality required careful configuration of the tablet press feeding system. The researchers tested different feeder paddle shapes and determined that standard paddles delivered the best tablet weight consistency. Once the feeding system was defined, the researchers carefully adjusted the punch penetration into the die bores to ensure adequate tablet strength in all minitablets produced. Because the parameters were optimized, the process performed best at the highest turret speed possible—90 rpm.
Coating formulation
A taste-masking coating formulation was prepared using a combination of Surelease (Colorcon) and Opadry (Colorcon), which are both well-known, fully formulated, and pH-independent aqueous polymers. Surelease contains ethyl cellulose, which is insoluble in water and acts as the taste-masking agent by delaying the release of the drug in the mouth. Also, as a non-ionic polymer, ethyl cellulose provides very low potential for drug interactions.
Opadry is HPMC based and acts as a pore former in the coating, allowing immediate release of the drug once the tablets reach the stomach.
An 80:20 Surelease-to-Opadry ratio was suggested by the supplier. The coating formulation was prepared by dispersing the Opadry in deionized water and then adding it to the Surelease to achieve a total solids content of 12 percent w/w. Due to the high total surface area of the minitablets, a 10 percent weight gain was required as a process target. Table 1 shows the coating formulation parameters for both the pilot and production batches.
Coating application
Pilot coating tests were performed to investigate the coating formulation and determine the right parameters for a 20-kilogram batch. The pilot tests were conducted using an IMA Perfima Edge Lab coater with a 30-liter drum. This side-vented pan coater is specifically designed for coating small substrates such as pellets. The coater maintains the same drum shape, geometry, and spray system as a stan- dard tablet coater, but the drums are constructed using a slotted, wedge-wire screen that allows air to pass through the drum during coating. Specially designed mixing baffles welded to the drum’s center and sidewalls allow the coater to handle a variety of substrates with different shapes and sizes.
The pilot tests were done in triplicate to confirm process repeatability before scaling up. The process parameters were harmonized to maintain a stable tablet temperature of 42° to 45°C, and the process time for a 10 percent weight increase was less than 3 hours for each trial. Because the process parameters were optimized, the final yield for each trial was in the region of 99 percent. Once the parameters were fixed, the coating process was scaled up and performed using a production-scale IMA Perfima Edge coater with a 200-liter wedge-wire screen drum. Table 2 shows the coating parameters for both the pilot-scale and production-scale coaters. Scaling up from lab to production scale was easy because of the similar geometry between the pilot and production drums.
Conclusions
The coated minitablets produced in this study showed no visual defects or surface roughness. The combination of Surelease and Opadry resulted in an easy-to-apply coating that can be quickly and easily modified by adjusting the percentage of pore former and the coating weight gain to obtain a range of drug-release profiles. All materials used in this study have precedence of use in pediatric applications.
The tableting process was challenging compared to standard tablet compression, but it was stable and not problematic. The slotted-screen drum design proved to be a suitable technology for coating minitablets for taste-masking purposes. The coater has a much smaller footprint for the same batch size than a fluid-bed coating process, and the spray guns are accessible during the process. The drum did not cause abrasion or damage to the minitablets and allowed for a high inlet-air volume and a high spray rate, resulting in economical process times similar to those of conventional perforated-drum coaters. Additionally, the process is easily controllable, which simplifies scale-up.
References
1. C. Funaro, G. Mondelli, N. Passerini, and B. Albertini, “Minitablets coated in a solid-wall pan for the- ophylline sustained-release capsules,” Pharmaceutical Technology, 2010, No. 6, pages 38-42.
2. L. Baginski, F. Bang, T. Cech, F. Cembali, C. Funaro, and G. Mondelli, “Evaluating an alternative to fluid bed technology for drug layering and for applying functional coats onto pellets,” 39th CRS Annual Meeting, 2012.
3. D. V. Diad, V. Ambudkar, R. Steffenino, T. Far- rell, and A. R. Rajabi-Siahboomi, “The influence of pore-former on drug release from ethylcellulose coated multiparticulates,” 37th CRS Annual Meeting, 2010.
4. J. Teckoe and A. R. Rajabi-Siahboomi, “Investigation of Taste Masking Performance of an Aqueous Ethyl- cellulose Dispersion (Surelease Ethylcellulose Dispersion Type B NF) on Acetaminophen Granules,” AAPS Annual Meeting, 2013.
5. “Use of Surelease and Opadry in the Development of a Paediatric Form of Raltegravir for the European Union,” Colorcon website: www.colorcon.com.
6. “Film Coating for Pediatric Oral Solid Dosage Forms,” White Paper, Colorcon website: www.colorcon. com.
7. Herbert A. Lieberman, L. Lachman, and J. B. Schwartz, Pharmaceutical Dosage Forms: Tablets, Vol.1, 2nd Edition, CRC Press, pages 387-391.
8. Bob Oas, “Making bitter-tasting APIs palatable using the right combination of excipients,” Tablets & Capsules, July 2006, pages 12-18.
Federica Giatti is process development technologist, R&D laboratory, Massimo Malavolti is product manager, coating equipment, Fabriano Ferrini is product manager, tableting and encapsulation, and Caterina Funaro is process laboratory manager at IMA Active, a manufacturer of solid dose process- ing equipment (+39 051 6514111, www.ima.it).