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

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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.


Pharmaceutical Technology


An important feature of the Xcelodose manufacturing equipment is that they check every capsule's weight for acceptance or rejection. The microbalance not only supports the accuracy and sensitivity of the device, it also allows for setting acceptance and rejection parameters. The need for a weight-sorting step in the manufacturing process is thus eliminated. The weight-checking traceability, with a printability option, of each capsule manufactured simplifies the capsule count required at the end of the batch for yield-check calculations.

In addition, the Xcelodose process for filling API into capsules reduces analytical-method development time because the capsules are tested for moisture content, assay, and impurities. The necessity of testing for content uniformity of the capsules is a regulatory concern because each capsule is zeroed before the API is dispensed, and the system automatically rejects filled capsules that are outside the set weight-variation range. The time needed to qualify an assay and impurities method is short because of the absence of excipients. Even the API assay method can be qualified for product release, provided the amount of API in the capsules is not low. A low amount of API might require dissolving the capsule to obtain the complete amount of API in the flask. All these aspects reduce the time needed for chromatographic analysis. A quick disintegration test may be sufficient for dissolution testing, rather than a complete dissolution method. Lastly, if the amount of API in a capsule is low, then moisture-content testing will require a large number of capsules.

The capsule filler's software is designed to meet 21 CFR Part 11 audit-trail and password-protection requirements. Because a specified amount of API is weighed into each capsule, the process produces minimal wastage compared with tablet presses or encapsulators. Little API remains in the hopper, which minimizes loss.

Drug in a bottle

Often an API is poorly water soluble and has poor dispersibility characteristics, which makes reconstitutable suspension an option. If the API is soluble in one of the readily marketed oral syrup vehicles such as "Ora-Sweet" (a combination of sucrose, glycerin, and sorbitol, Paddock Laboratories, Minneapolis, MN), then the filling of the dispensing bottles with an API may be an option to consider. The technique does not involve formulation work, and because the dispensing bottles are only filled with the API at the contract research organization's (CRO's) site, it saves time and cost. A pharmacist or clinician administering the dose can dilute filled bottles with Ora-Sweet or a polymer dispersion containing methylcellulose, sodium carboxymethylcellulose, or mineral oil. Another advantage of the dispensing-bottle option is that multiple doses can be dispensed in the clinic and taken home by patients, if required. Reconstituting multiple doses at the clinic means less frequent visits of the clinical subjects to the clinic site.

One option for evaluating taste is using an electronic tongue (e.g., "Astree Electronic Tongue," Alpha M.O.S., Toulouse, France). The electronic-tongue taste evaluation quantifies the bitterness of the API, helps develop suitable matching bitter placebos for blinded clinical trials, and helps optimize taste-masked formulations (3). This investigation may lead to the inclusion of a sweetener such as sucrose, fructose, a polyol (sugar alcohol) such as mannitol, or a high-intensity sweetener such as aspartame or saccharine (4). It may be necessary to include an excipient such as ethanol or glycerin to wet the surface of the API particles before the vehicle is added, thereby increasing the API's solubility in the vehicle.

Filling API in a dispensing-bottle manufacturing process is neither complicated nor time-consuming. The time for assay-method development is short because excipients interfere less during method qualification. The exicipients may be a sweetener and a vehicle such as Ora-Sweet. When a bottle contains API and excipients, a minimum amount of developmental stability data are needed because the API in a bottle is manufactured in a CRO facility and the volume is prepared by the pharmacist or a clinician administering the dose. Once the bottles are prepared at the clinic and given to clinical subjects, they are consumed in a specified amount of time, which further reduces the requirement for developmental stability data. The general tests are appearance, completeness of solution, pH, microbial limits, assay, and impurities.

If early clinical data indicate a need to bypass first-pass metabolism, spraying a suspension below the tongue mucosal area is suggested (5). Considerations of taste-masking, solubility, mucoadhesive excipients, and local irritation by the API should be evaluated before choosing the approach of spraying a suspension. A quick evaluation using an electronic tongue and a Franz-type diffusion study should be conducted to provide additional taste and mucosal-layer diffusion data (6).


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