« FORMULATION DEVELOPMENT/INSTRUMENTATION
Depakote®. Amorphous screens are typically last on the list, due to physical and chemical stability considerations. Typical apparent solubility enhancement of 2× exist for polymorphs, 0.1 to 1000× for salts and cocrystals, and 2 to 1000× for amorphous material compared to the crystalline API.4
Amorphous and cocrystal screens can be
conducted in parallel with the salt and polymorph screens if sufficient resources and material are available.
Generally form screening should be considered a tradeoff between thermodynamic and kinetic properties. The drug must be reasonably stable and sufficiently bioavailable. If the drug is too stable, it will not be soluble enough nor will it be bioavailable. Should the drug be too soluble in water, it would tend towards being hygroscopic and may potentially be unstable. The process chemist desires a material that readily crystallizes while the formulation scientist desires a material that tends to crystallize slowly in the GI milieu subsequent to the dissolution in order to maintain supersaturation.
In addition, there may be differing requirements for the API depending on the project stage. Toxicity concerns are of paramount importance during discovery and early development because a safety margin must be established. Typically this margin requires dosing API at 10 to 100× the expected efficacious dose. Thus, solubility is typically emphasized. The human efficacious dose is established during Phase I or Phase II depending on the indication. Long-term considerations such as API and drug product stability become important. The more soluble polymorphs are less stable physically, or potentially even chemically, than the thermodynamically stable form.
The form requirements should also take into account the solubility targeted, dissolution rate needed, stability of the compound, and melting point. Ideally the type of dosage form to be developed, the route of administration, and loading in the drug product are also considered. Toxicology of the coformers should be considered for salt and cocrystals.
Form screening should be an iterative process.2 Early screening
should be conducted to support tox and first in human (FIH) studies. A secondary screening process should be conducted, if needed, to determine final form, utilizing the data from the early screening studies and the exposure data from the tox and FIH studies. While formally presented as 2 separate stages, the 2 screening activities are part of a continuous effort towards form screening and monitoring. The second set of more comprehensive screening activities begins as soon as material is available. An even more comprehensive screen to be started during Phase II can be considered for intellectual property purposes. Each succeeding screen becomes more comprehensive than the previous screen requiring more material, more manpower, and more time than the previous work.
Form screening is still an empirical process. The perfect plan for form screening therefore requires an infinite number of experiments. In addition, it would require more material, time, manpower, and would provide for the final form for development as soon as the lead candidate has been identified. This, of course, is not possible. Rather, the form screens must provide, at a minimum, answers appropriate to the next project phase.
Polymorph Screening
The assumption in early development is that there are limited materials and limited resources. A stable form screen should be conducted with emphasis on hydrate formation and solvate formation from solvents used in the preclinical process.5,6
formulation and chemical The screening experiments should be conducted at or near
equilibrium conditions. Typical experiments would include slurries, slow evaporations, and some slow cooling experiments.1
Solvents
would include water and water containing solvents, solvents used in the formulation process, and solvents of a wide range of polarities and hydrogen bonding and acceptor propensities. Experiments should be conducted at room temperature or at the storage temperature of the formulation. Typically 20 to 30 manual experiments should suffice or 100 or more automated high-throughput screens (HTSs). HTSs have the advantage of using many more conditions.7
The disadvantage is
that HTSs require optimization to get good analytical data and require scale-up to fully characterize the solids.
It is possible to acquire more than just form data from the form screens. Some solubility data can also be gleaned by observation for solution experiments. More accurate data are collected from slurry experiments either by high-performance liquid chromatography (HPLC) analysis or by gravimetric analysis using thermal gravimetric analysis (TGA). Information on purification can be obtained by conducting HPLC analysis on both solids and the solution. For evaporation experiments, this requires analysis of the solution phase after solid formation has begun and prior to complete evaporation. We prefer to analyze the solids while they are still damp with solvent. This increases the probability of finding solvates and metastable forms. Therefore, it is preferable not to carry evaporations out to dryness.
Compressibility, flow, and compatibility with
excipients are also important. There are few perfect forms for all stages of pharmaceutical development.
The solids are analyzed by polarized light microscopy (PLM) to determine crystallinity and morphology. X-ray powder diffraction (XRPD) or Raman spectroscopy is used to determine the form. A thermal screen is conducted on the solids using differential scanning calorimetry (DSC), TGA, and hot-stage microscopy if the isolated form does not correspond to a previously known polymorph. Hot-stage microscopy may help determine if an isolated form is a solvate. Many solvates crack or become opaque when heated or dried.
Salt Selection
Salt selection can be done after the initial polymorph screen has been completed or, if material is available, in parallel with the stable form screen.8-9
The salt screen is also abbreviated. Typically 4 to 8 acids
would be initially chosen for evaluation using a manual screen and at least 8 to 12 for an HTS. Salt selection would stop after 1 or 2 potential candidates have been found due to material and resource limitations. Each salt attempt for a manual screen should be conducted in at least 4 sets of conditions using different solvents with the type of experiment depending on the solubility of the salt. Generally the free base or free acid should be soluble in the solvent chosen and, ideally, the salt insoluble. Recommended solvents include one of the acetate esters such as ethyl acetate and a ketone solvent such as MEK since
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