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FORMULATION DEVELOPMENT/INSTRUMENTATION
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many salts have low solubility in these solvents. An HTS should use 8 to 12 different solvents or mixed solvents per salt attempt. Recent analysis indicates that rational salt selection may have an advantage over the HTS screens despite utilizing fewer experimental conditions.10 A stable form screen should be conducted after the potential salt has been identified.11
Samples are also analyzed while still damp with
solvent, as explained above. Salt
formers are generally chosen based on the pKa differences
between the acid and base. The general rule is that the pKa difference should be at least 2 to 3 units.12
Smaller differences than this can
still lead to salt formation or may lead to cocrystal formation. The counterion should be pharmaceutically acceptable. Not all salts listed in the standard references may be acceptable.12 for salt formers are available.12
Frequency charts Some of the salt formers used in the
past are no longer used. It is best to consult with toxicologists about unusual salt formers.13
The Orange Book is a good source for currently
used salt formers and also contains information on the amount of salt former used.14
A more comprehensive form screen should be conducted after the initial abbreviated screen. The initial screen was designed only to provide an acceptable form for toxicology considerations. The purpose of this screen is to determine the form for Phase 1, and possibly later, development and to guide the process chemists as to solvent choice for crystallization. The key stakeholders are both formulation and process chemists. Experiments should utilize a more comprehensive range of solvents including all FDA class 3, many FDA class 2 solvents, and other solvents favored by your company’s process chemists. Experiments should be expanded to use non-thermodynamic conditions such as rapid cooling, rapid addition of antisolvents, and fast evaporations.1 Experiments should also now encompass formulation process issues such as compression, milling with or without water, drying, and wet granulation.15
process development and to avoid potential
The idea is to identify and avoid potential solvates for formulation issues.
An excipient screen should be conducted, and preliminary stability assessed for the API form chosen.16
The thermodynamic stability of a salt in the presence of water is determination by its pH max.12
from the pKa
intrinsic solubility of the free form.12 2±1 pK units lower than pKa
for a weakly basic API. The salt is stable below
pH max, and the free form is stable above it. A typical tablet formulation contains water along with excipients many of which are ionizable or contain polar groups. This leads to a change in the local pH around the excipients compared to the bulk. Typical micro environmental pH values range from 4 to 7.5.17
The high micro environmental pH may cause the
salt to convert to the free base if the micro environmental pH is above pH max and lead to a loss in bioavailability. This is one reason why we do not want to force all API to be salts.
Cocrystals
Cocrystals are considered for development when salt formation is not an option (non-ionizable API), the salt or free form of the
56 | | January/February 2015 The pH max of a salt can be calculated
of the free base or acid, the solubility of the salt, and by the The rule of thumb is that pH max is
API has too low or too high solubility, the API or its salts have undesirable properties, the API cannot be crystallized, purified, chirally resolved, etc, and for intellectual property reasons.
Cocrystal screens are, in principle, similar to salt screens with the caveat that cocrystal formation may occur over a narrower range of conditions.18
for cocrystals is more comprehensive than salts due to the relative uncertainty of cocrystal
formation compared to salt Suitable methods for screening include (solvent drop)
grinding, slurry methods, evaporation, cooling, melting (Kofler and DSC methods), and API-coformer solubility method.19-26
Screening formation.
Coformers are chosen based on different motifs such as hydrogen bonding, π-stacking, etc. Such motifs can be found or confirmed by searching the Cambridge Structural Database. Recommendations for coformers include, in general, pharmaceutically acceptable acids and bases and generally regarded as safe compounds. Acceptable levels of many compounds such as the parabens are being lowered so consultation with toxicologists should be done to find acceptable coformers.
The thermodynamic stability of non-ionizable cocrystals in suspension is determined by the eutectic point.27
The solid API and cocrystal are
in equilibrium at the eutectic point. For a 1:1 non-ionizable cocrystal, the ratio of the concentrations of the coformer to API determines the stability of the cocrystal.28
The pHmax of a cocrystal is
defined analogously to a salt. The solubility of the cocrystal is higher above pH max for an acidic coformer. Solubility for a basic coformer is higher at lower pH.
Further screening is required for cocrystals after their discovery. A polymorph screen will need to be conducted to identify potential forms. The phase diagram needs to be created to aid in scale up of the cocrystal and to help determine the formulation process.31
Amorphous Material
Amorphous material typically has a higher apparent solubility at the cost of potential physical and chemical instability. Amorphous material is typically generated from rapid evaporation such as spray drying, rapid evaporation using reduced pressure and a high vapor pressure solvent (low boiling point) under vacuum, and by lyophilization.32-34
Rapid quenching of the melt has also been used, but
this requires stability at the melt a property which many APIs do not have. Amorphous material may also be observed during polymorph screening from solvents in which the API has high solubility and which have a relatively low boiling point.
Solid dispersions are developed to aid in physical and potentially chemical stability.33-34
Dispersions consist of API and a stabilizing agent,
typically a pharmaceutically acceptable polymer. Solubility parameters are important in understanding the miscibility of the dispersion, but the data are typically not known at the early screening stages.35 Therefore, an empirical screen is typically done where multiple ratios of API and polymer are generated by rapid evaporation using either well plates or vials in a centrifugal evaporator or by lyophilization. PLM
Excess coformer is needed to stabilize the
cocrystal if the concentration ratio is >1. The pH-dependent solubility is observed for ionizable coformers.29-30
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