Pre-Formulation

PRE-FORMULATION DATA PACKAGE

Before conducting pharmaceutical drug product formulation activities, pre-formulation studies are initiated. During the pre-formulation phase, the physical and chemical properties of the active pharmaceutical ingredient (API) are determined. The knowledge gained on the API helps to select the right salt or polymorphic form, and supports the design and development of an initial dosage form, both for pre-clinical and clinical use. Ascendia's pharmaceutical science team characterizes the drug candidate by evaluating its solubility profile, physical and chemical stability, and potential salt forms; and identifies impurities and degradation pathways. Characterization of the API during pre-formulation may include determination of: dissociation constant (pKa), partition coefficient (Log P), BCS classification assessment, particle size and morphology (laser diffraction, microscopic imaging), crystallinity (X-ray diffraction), thermal properties (melting point and glass transition), solubility studies in organic and pharmaceutical solvents (at various pH and in simulated media), excipient compatibility studies, and forced degradation studies (heat, acid, alkali, light, peroxides, metal ions).

Ascendia can generate the data needed for your CMC package in support of an IND filing, and the data guides the development of small-scale formulations for in vivo pharmacokinetic, efficacy, and toxicology studies or proof-of-concept testing.

SMALL-SCALE FORMULATIONS FOR PRE-CLINICAL TESTING

Ascendia develops and evaluates a variety of formulations for preclinical non-GLP and GLP studies. We understand the needs of companies with an exciting compound in the discovery pipeline, but with limited amounts of drug substance. We have developed methods for carrying out formulation screening studies with as little as several mg of drug substance. These methodologies can be used to formulate new drugs for initial in vivo experiments when only low milligram quantities of the drug have been synthesized and/or purified.

After screening, our formulation development includes feasibility studies to determine compatibility of excipients, active ingredients and delivery components, formulation selection, and optimization. We provide statistical experimental design, short-term and accelerated stability studies, and analytical method development and validation. Using our expertise in modeling and simulation (e.g., GastroPlus and WinNolin), we can predict the animal PK profile and propose an efficient formulation strategy for preclinical studies accordingly. Often these small-scale formulations are provided in liquid form, developed for various routes of administration (oral, iv, ip, sc, etc.).

Solutions

Depending on the drug candidate’s solubility properties, lipids, surfactants, complexation agents, and co-solvents can be added to increase solubility, and hence enhance solubility and bioavailability for initial animal testing.
 

Suspensions

Particle size and selection of a suspending vehicle are frequently critical factors impacting the stability and dissolution rate. Micronization of the drug substance by jet milling, or wet milling in a suspending vehicle, can therefore be important to obtain good bioavailability of a poorly water soluble drug substance.
 

Nano-suspensions

Preparation of nano-suspensions of a poorly water soluble drug substance further increases the dissolution rate (by increasing the surface area). A nano-suspension of a poorly water soluble drug substances may show a faster dissolution rate and a higher solubility/bioavailability when compared to a micronized suspension.

Emulsions

If dictated by solubility data (in oily vehicles, co-surfactants and solvents), an emulsion – a fine dispersion of oil droplets – can be formulated to improve the initial probability of success. The drug may be dissolved or suspended in either the oily liquid, formulated as an emulsion, and/or then further incorporated into solid matrix or aqueous liquid phase.
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