Recent Options for Phase 1 Formulation Development and Clinical Trial Material Supply

To meet the demands of early-stage development, contract research organizations can evaluate various dosage-form options. The author examines various methods of capsule filling, including binary blends.
Aug 01, 2008
Volume 2008 Supplement, Issue 3

Paul Taylor
Large and small pharmaceutical companies as well as emerging companies that may operate as virtual companies strive to shorten drug-development times. The ability to hasten drug development is particularly important for virtual pharmaceutical companies, which focus on drug discovery and development but rely heavily on outsourced services to perform the functions necessary to move a drug through development to commercial manufacture. The ability of these companies to stay competitive depends on transforming new chemical entities into clinical products. The increase in the number of virtual companies has resulted in enormous investments in investigational new drugs. The active pharmaceutical ingredients (APIs) coming out of synthesis are challenging formulators' abilities to develop dosage forms.

Scientists have developed various methods to improve preformulation properties. The situation remains challenging: About 60% of compounds in development are poorly soluble. The literature reports that one-tenth of marketed drugs have solubility problems, more than one-third of drugs in the pipeline are poorly soluble, and nearly two-thirds of drugs coming directly from synthesis have low solubility (<0.1 mg/mL) (1). Poor solubility contributes to dissolution problems. Another challenge has been APIs with poor flow characteristics. All these aspects of the traditional dosage formulation-development process present challenges and increase the amount of time it requires.

Outsourcing early formulation development and clinical trial material manufacturing is an important strategy for virtual pharmaceutical companies and for larger pharmaceutical companies that seek to reduce cost and time in early drug development. Several options for dosage forms may be used in early-stage formulation development, including API in a capsule, drug in a bottle, liquid in capsule, and binary blends.

API in a capsule

Filling an API directly into a capsule is probably the quickest and best option for entering clinical trials. This method offers the advantage of having little or no need for excipients, thereby potentially saving as much as six months of formulation-development and stability-testing time At the early clinical phase, the API manufacturing process is often altered, and lot-to-lot variation in the physical characteristics of the API is common.

Filling API into capsules is quick for noncohesive APIs with good flow characteristics. These APIs do not need a flow-aiding exicipient or a physical processing step. Interestingly, it takes less time to implement a processing step for high-dose APIs than for low-dose APIs, which require a manufacturing process that enables them to meet content-uniformity criteria. Excipients are included only to improve the physical characteristics of the API but not to modify the chemical characteristics with antioxidants, buffers, chelators, or moisture scavengers. If an excipient is needed to influence chemical characteristics, then the project path can lead toward a routine formulation-development process, which can help overcome dissolution and content-uniformity challenges.

However, the API in a capsule approach does not involve developing a dissolution method or conducting content-uniformity testing. Thus the approach saves time that would have been spent on analytical methods and formulation. Of course, if the approach is successful, then additional time is saved in ordering, receiving, testing, and releasing the excipients as well as writing and approving specifications. The approach is suitable for both gelatin and hydroxypropyl methylcellulose capsules. It is a matter of getting one capsule type and API lot released for clinical use and creating an approved batch record.

Figure 1
One type of filling equipment is the "Xcelodose 600 S" (Capsugel, Peapack, NJ, see Figure 1) microdosing system, which can fill amounts as low as 100 μg at speeds of more than 600 capsules/h at lower than 2% RSD weight range (2). In general, the equipment is approximately 10x faster than filling by hand and provides 50% greater throughput than an the earlier "Xcelodose 120 S" system (Capsugel). The tapping, dispensing head, movement of the dial plate, and the turret system provide accurate dispensing into a capsule shell. A microbalance makes the filling process suitable for dispensing precise microquantities. The Xcelodose 600 S model fills into vials, tubes, blisters, and cassettes and can fill granules or beads in a capsule.

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