Addressing solid-dose manufacturing trends
Several emerging trends in solid-dose manufacturing may be more easily overcome by OTF formats than other solid forms. A push
toward developing low-dose, high-potency formulations (6) is leading to improvements in drug formulation. These include the
conversion of drug substances to new forms such as from salt- to free-base, modified crystal morphology, and nanoparticles,
which may present challenges for traditional solid-dose manufacturing. For example, nanoparticle drug substances may segregate
more easily than micronized counterparts during the powder-blending and powder-flow processes that lead into the direct-compression
operations in solid-dose manufacturing. Because APIs typically are added into bulk fluids in various ways before casting OTFs
(suspensions, emulsions, or solutions), new high-potency drug forms do not present any unique barriers to OTF formulation
and manufacturing.
A second trend is the increasing need for dosage formats using poorly soluble drugs (6). One solution to improving poorly
soluble API delivery is through particle-size reduction such as nanoparticles. Other mechanisms include preparing the drug
substance as a microemulsion or using co-solvents to solubilize the API. OTF formats can accommodate any of these techniques
during manufacturing.
Flexibility in formulation
An inherent benefit of the OTF format to drug manufacturers is the flexibility of film formulation for a wide range of eligible
APIs. A number of physical properties can be altered, including film-dissolution rates, material composition, and API absorption
rates (5).
Figure 1
|
Customizing dissolution rates.
OTFs are produced by combining water-soluble components and additives to attain a desired dissolution rate when exposed to
a fluid. By modifying the combination of film-forming polymers and film thickness, formulators can design films to release
their APIs in seconds, or for controlled-release applications, to deliver the dose over a period of hours (see Figure 1).
Formulators may select materials from several water-soluble polymers to deliver the desired film strength and disintegration
properties. Examples of water-soluble polymers include natural gums, polyethelene oxide, derivatives of cellulose, polyvinyl
pyrrolidone, polyvinyl alcohol, and acrylic-based polymers (7). The optimal properties of film strength and disintegration
are obtained with the selection of a particular combination of hydrophilic polymers.
Material sets are tailored to meet specific guidances and regulations. Scientists have various formulary options to address
regulatory and compliance needs including, but not limited to:
- Bovine spongiform encephalopathy/transmissible spongiform encephalopathies (BSE/TSE)
- Nongenetically modified organisms (non-GMO)
- United States Pharmacopeia (USP)
- European Pharmacopoeia (EP)
- Japanese Pharmacopeia (JP).
Analytical methods exist to characterize specific products and the potential impact of material selection on a product's performance.
Thickness and mass play a role in the determination of dissolution rates. Constructions composed predominantly of low-MW,
water-soluble polymers at different thicknesses will result in a range of rapid disintegration rates and mechanical strengths.
High-MW polymers tend to impart good mechanical properties; however, disintegration time is increased (9).
Future applications may require films that demonstrate specific dissolution rates to release drugs in different physiological
conditions (e.g., neutral–alkaline pH). Such appliations can be created by adjusting film thickness or adding excipients that
control the release. Dispersed-phase filler particles can be included to add bulk to the film, increase the solids portion
to facilitate coating, or alter dissolution rates. When distributed throughout the film layer, air or other gases can also
change the dissolution time (10).
Material options for API liquid casting
. The flexibility of the OTF delivery format provides an unlimited set of raw materials to select from when developing and
delivering APIs. These materials include traditional aqueous-soluble and solvent-soluble (nonaqueous soluble) ingredients
(2). API-containing liquid formulations may be in the form of a solution, emulsion, suspension, or dispersion.
- Solutions: all ingredients, including drug substances, are fully dissolved and soluble in the bulk liquid
- Emulsions: these are typically used for aqueous formulations to which an oil-soluble ingredient such as a flavoring has been
added
- Suspensions or dispersions: nonsoluble APIs or other excipients may be added to the bulk-liquid formulation under careful
controls before casting to assure the dispersed phase remains suspended for uniformity.
|
