Introduction
In early phases of development, only small amounts of the active pharmaceutical ingredient (API) are available. With difficult drugs however, many different formulations are necessary to achieve adequate bioavailability. Therefore, low API consumption for each formulation creates a substantial developmental advantage. This can be achieved by miniaturized equipment for the most relevant pharmaceutical technologies. Until a few years ago, the commercially available equipment required minimal batch sizes of 50 – 100 g for nearly all formulation technologies. Number of small scale equipment increased considerably in the meantime, but in most cases, the basic technologies are still designed for large scales, only the formulation part is smaller. Therefore, this equipment is still very expensive, heavy, and requires a lot of lab space and cannot be located easily into containments which is necessary for toxic or highly active APIs. Therefore, miniaturized equipment for the most relevant formulation technologies of oral dosage forms was developed at the group new technologies of Boehringer Ingelheim (BI).
Selection of Most Suitable Excipients
Selection of excipients for poorly soluble drugs in miniaturized scale and dissolution testing thereof was already described in my previous article, “Dissolution Testing of Solid Products” [1].
Miniaturized Dissolution Testing Using Wellplates
When dissolution testing has to perform with extremely small amounts of formulations, either 24, 12 or 96 wellplates are preferred dissolution vessels, as buffer volumes employed are only 3, 1.5 or 0.2 ml. Most suitable dosage forms are granules, pellets or extrudates. Dissolution profiles are obtained by shaking the wellplates in commercially available shakers with adjustable temperatures, quantification employs UV-reading in multichannel Elisa readers. UV reading can be done directly in the dissolution wellplates or after transfer of small volumes into e.g. a 384 wellplate. Details of evaluation are given in my previous article [1]. A photo is displayed in Figure 1.
Miniaturized Granulation Equipment
Wet granulation is an important step for tabletting. A miniaturized granulator which is very small, cheap to produce, well scalable at it works in an identical way as production equipment and rapidly cleaned is shown in Figure 2.
Miniaturized Extrusion Equipment
Extrusion in general offers several advantages over other production technologies:
• High loads of drug (and functional excipients) of up to 100% are achievable
• The high energy input achieves increased dissolution properties additionally to the effect of dissolving and supersaturating agents
• Due to the simple and robust technology up scaling is rather simple
• It is a continuous process with high output with even small extruders
• Multiparticulates as well as tablets can frequently be produced in one production step
• Even though extrusion in pharmaceutical production is just gaining wider distribution, due to the wide application in food and plastics industry the technology is quite mature
Figure 3 displays the impact of extrudation conditions on the dissolution performance of a poorly soluble week base at the pH of minimal solubility of batches with identical composition. The composition contains API, pH modifiers and supersaturating excipients.
Therefore extrusion is an important technology in formulation development. As no feasible equipment is commercially available, corotating twin screw extruders with screw diameters of only 12, 9, 8 and 5 mm were developed, which are the smallest commercially available extruders worldwide. Barrels of these twin screw extruders are shown in Figure 4.
In order to get small pieces of the formed extrudates with a length to diameter (L:D) ratio close to 1, which can be filled directly into capsules or further processed to tablets, a miniaturized face cut system was developed which is shown in Figure 5.
If the extrudate is directly formed to tablets, very high drug loads can be achieved, as no fillers or disintegrants are necessary. A miniaturized calendar system is shown in Figure 6.
Miniaturized Equipment for Pellet Layering and Coating
If excipients (e.g. acids or bases in case of pH-dependent solubility) which improve dissolution of poorly soluble APIs cause decomposition of the API, stable products can be achieved by physical separation of the API and the excipient. This can be achieved by pellet layering: A core of the excipient which can have an additional separation coat is layered with API by spraying a solution or suspension of the API onto the starter pellets and with further coats if necessary. Thus APIs and excipients are completely separated during production and storage which improves stability. After oral intake, the gastrointestinal fluids penetrate into the pellets, dissolve the excipient, and then the excipient’s solution then dissolves the API, which improves bioavailability. Miniaturized equipment for pellet layering is shown in Figure 7. Preferred spraying systems employ a modified airbrush piston which is commercially available and has narrow spraying angles. Thus very small diameters resulting in small batch sizes can be achieved. The device is displayed in Figure 7.
Simulation of Spray Drying
Spray drying is a suitable technology for poorly soluble drugs as it frequently results in amorphous API which improves solubility and thus also bioavailability. If a solution containing excipients and API is sprayed slowly directly into a preheated metallic wellplate (Figure 8), evaporation occurs within milliseconds and thus reflects the condition of spray drying. “Batch size” in this case reflects the necessary amount of API for dissolution, which means it is extremely slow. As dissolution can be directly in the wellplate, high throughput for formulations is achieved. If more solid formulation (e.g. for further processing) is needed, the API solution is sprayed repeatedly into a preheated metallic plate and scratched of when enough material is available.
Miniaturized Conical Planet Mixer Planet
mixers are very suitable if very intensive mixing for longer times, e.g. for incorporation of API into cyclodextrines is necessary. It consists of two counteracting screws and the total stirring device rotates relative to the vessel in order to achieve complete and homogenous mixing. Due to the conical shape very small batch sizes of 3-5 g are feasible. The complete device is displayed in Figure 9 (left side), the stirring screw and the conical vessel on the right side.
Miniaturized Melt Embedding
Melt embedding at scales of 0.2 – 1 g can be achieved by drilling round holes into a heatable metallic plate, stirring is done by small splitted spatulas.
Summary and Conclusion
Miniaturized but scalable equipment was developed for the most relevant formulation technologies. Main advantages are:
• Low API consumption per batch
• High throughput for formulations and dissolution as production of formulations and cleaning of equipment is much faster than with commercial equipment
• Less consumption of lab space
• Equipment can easily be transferred into containments.
A survey of minimal batch sizes compared to standard procedures is displayed in Table 1. An example for comparison of cost of goods per formulation is given in Table 2.
The substantial advantages of miniaturized equipment are obvious.
References
1. R. Brickl, “Dissolution Testing of Solid Products.” American Pharmaceutical Review, Vol.13, Issue 1. 2010, 98 - 102
Author Biography
Rolf Brickl, PhD was born October 8, 1944 in Munich, Germany. He received his Diploma in 1969 and his Ph.D. in 1971 in Physical Chemistry at Tachnical University Munich.
He has worked at Boehringer Ingelheim Pharma GMBH & Co. KG since 1972 in the fields of Dermatological Research, Human Pharmacokinetics and Pharmaceutical Research and Development. Rolf is a scientific expert in formulation and kinetics of extended release formulations and poorly soluble drugs, development of high throughput formulation technologies and dissolution technologies, development of miniaturized formulation, and dissolution equipment.
He has created many patents, written papers, and given presentations at international meetings, and he is the winner of Boehringer Ingelheim Research and Development Award in 2004 and of German Development Award Boehringer Ingelheim in 2008.