Small Molecule Drug Development:
Formulation & Process Development
Parenteral Dosage Form Development
Physicochemical properties of the drug, as well as the route of administration, determine the formulation strategy for parenteral dosage forms. Parenteral dosage forms are typically administered by injection intravenously, subcutaneously and intramuscularly, as well as less common administration routes. Each route of administration introduces subtleties to the formulation design and significant restrictions on vehicle selection and dosage volume and requires sterile product. The types of formulations are quite broad and include liquids, suspensions, emulsions, lyophilized products, nanoparticles, liposomes and implants. Ideally, the formulation is isoosmotic and has a physiological pH, characteristics which minimize pain upon injection. However, this ideal formulation is rarely realized due to the solubility and stability constraints of individual molecules. For these reasons, Wolfe Laboratories uses excipients to confer increased solubility and/or stability. Such approaches could include pH modification, cosolvents, non-aqueous vehicles (for intramuscular products), surfactants, complexation agents and emulsions. In addition to physical and chemical stability of the formulation, parenteral dosage forms also require stability in relevant sterilization, storage and administration equipment.
Lyophilized Dosage Forms
Lyophilized dosage forms are frequently used to mitigate stability issues. Development of lyophilized formulations requires selection of suitable excipients such as bulking agents that will deliver a pharmaceutically elegant and physically and chemically stable dosage form. If pH modification is required, the buffer selection may need to be modified to account for volatility of the components and compatibility of concentrated ingredients.
Oral Dosage Form Development
The general approach towards oral formulation development involves first assessing simple formulations and increasing the complexity, if needed, until sufficient performance is obtained. Wolfe Laboratories then optimizes dosage form composition and adjusts analytical methods.In collaboration with the sponsor, Wolfe Laboratories conducts a proof-of-concept (POC) PK study using the prototype formulations. Upon evaluation of the PK data, the team determines whether the results justify refinement of the prototype formulations. The dosage form is evaluated for its storage stability, and excipient component ratios are optimized for optimal in vitro performance. The performance of new prototype formulations are verified in vivo, after which process optimization ensues.
The simplest oral dosage form utilizes powder in capsule (PIC) whenever possible. However, when there is insufficient bioavailability, more complex formulation approaches may be warranted. The specific program design considers pharmaceutical and biopharmaceutical factors such as: aqueous, organic and lipid solubility, crystallinity, pKa, logP, food effects, permeability and efflux, non-enzymatic degradation in the GI tract, and metabolism. Consequently, the specific formulation design approach depends upon the attributes of a given molecule.
Considerations for Liquid Oral Formulations
Liquid dosage forms require that sufficient solubility and stability are maintained to support the dosing studies. If preformulation studies revealed sufficient solubilities, then developing a liquid dosage form is relatively straightforward, but if the solubility is insufficient, suspension dosage forms may be required. The formulation may also require taste masking and other excipients.
Considerations for Solid Oral Formulations
The success of solid dosage formulations depends on achieving the sufficient dissolution rate and stability of the physical form of the compound. Polymorphs can result in different solubility and dissolution properties, and thus adversely impact the bioavailability. The dissolution rate is dependent upon the intrinsic dissolution rate, the volume into which the drug must be dissolved, and the surface area. For poorly soluble drugs, it may limit the extent of absorption and therefore must be well understood. For the purposes of informing rational formulation development, the choice of the biorelevant media is also important.
Enabling Oral Formulations
Self-emulsifying drug delivery systems
Self-emulsifying drug delivery systems (SEDDS) generally contain oil, surfactant, co-surfactant and a co-solvent. Wolfe Laboratories evaluates compound performance in various blends to develop prototype and optimized formulations.
Amorphous Dosage Forms
Thorough characterization of solid-state properties and physical form stability reduces the risk in product development. In situations where poor oral bioavailability is caused at least in part by limited dissolution of the starting material, and if the starting material is crystalline, altering the solid-state from crystalline to amorphous state may lead to improved solubility by reducing the energy barrier to dissolution. The amorphous dosage forms can be formulated as solid dispersions, liquids or suspensions. A more complex approach involves development of a lipid-solid dispersion. Additives can increase or decrease the melting temperature for ease of preparation and affect the properties of the solidified material. At the manufacturing stage, the solidified melts can be pulverized into powder or melt extruded and then pulverized into powder, which can be compressed into tablets. Alternatively, liquid melts can be loaded into capsules and cooled.
Discovery Formulation Development
Discovery-stage formulations enable meaningful efficacy and toxicity assessment by maximizing exposure upon administration with minimal material usage. Discovery formulation screening is a useful precursor to formal formulation development and is appropriate for the lead selection/lead optimization stage of a development program, but it does not eliminate the need to perform rigorous quantitative pre-formulation and formulation development studies at a later stage. The formulation approach incorporates compound structure, physicochemical properties, desired administration route, total dose, dose volume and stability.