Solid State Considerations for Early Development

• Genentech

“The enemy of a good plan is the dream of the perfect plan.” Carl von Clausewitz

Introduction

Solid form screening has become an important activity in drug development. The initial screening activity is designed to find an acceptable physical form of the active pharmaceutical ingredient (API) for development.

This article attempts to describe a rational process, although imperfect, for form screening suitable for early development. It is an iterative process with screening activities becoming more comprehensive as more material and resources become available. Each portion of the screening process is designed to answer the key questions associated with the form for the next development stage. Its goal is not to find the perfect form but to find an acceptable form for development.

Screening Considerations

There are 4 basic approaches to developing a suitable form. They are development of (a) the neutral form (eg, free acid or free base) either as a non-solvated or solvated form; (b) a salt of the API, if possible, also as the non-solvated or solvated form; (c) of a cocrystal; or (d) amorphous material, either as pure amorphous API or as a solid dispersion with an appropriate carrier.^1,2

Many properties of the API are affected by the form chosen.³ Among these properties are solubility, hygroscopicity, color, melting point, dissolution rate, flow, filterability, compressibility, and excipient compatibility. The key criteria for form selection are: (a) exposure— typically related to dissolution rate and solubility, (b) stability—both chemical and physical as drug substance and drug product, and (c) ease of manufacture.

The preferred order of form for development is the free form—first provided the free form provides sufficient exposure for the intended studies. A salt form is next preferred since it may add complexity to the process. The polymorph screen of the free form can be delayed if stability or pH solubility problems are expected and salt selection can be started instead. Generally both polymorph and salt selection are conducted concurrently if material is available. The desire is to develop a crystalline material which is typically the most thermodynamically stable form—unless there are stability problems, or absorption is solubility-limited, or a higher rate of dissolution is needed (higher C_max or shorter T_max). Cocrystal screening is becoming more common although there is only 1 known cocrystal commercial product, 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. Compressibility, flow, and compatibility with excipients are also important. There are few perfect forms for all stages of pharmaceutical development.

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 formulation and chemical process.^5,6 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.

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 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 Frequency charts for salt formers are available.¹² 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 The idea is to identify and avoid potential solvates for process development and to avoid potential 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 The pH max of a salt can be calculated from the pK_a of the free base or acid, the solubility of the salt, and by the intrinsic solubility of the free form.¹² The rule of thumb is that pH max is 2±1 pK units lower than pK_a 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 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 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 for cocrystals is more comprehensive than salts due to the relative uncertainty of cocrystal formation compared to salt 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 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 The pH_max 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 and XRPD can be used to evaluate crystallinity. DSC can be used to evaluate miscibility on a small scale.³⁵ Solid-state nuclear magnetic resonance has recently been shown to be able to predict miscibility on the nanometer scale.³⁶ The amorphous sample must be stressed under temperature and humidity and then reexamined to determine if the dispersion is physically and chemically stable. Material with a glass transition of less than 50 to 75°C should not be developed.³²

Impurities

Process impurities can have a profound effect on the forms found during the screening activities. There are literature reports and many anecdotal reports that impurities can change the form isolated and result in the discovery of a more stable, and less soluble, form.³⁶ Typically one lot of purified API is used for form screening. It is highly recommended that different lots of API are used for the different screens, that polymorph screens should be repeated after changes in the API manufacturing process and that crude API be used for screening.

Comprehensive Screens

Comprehensive polymorph screens, salt selections, and cocrystal screens should be conducted after completion of the preliminary screens.¹ These screens may include specialized screening and are beyond the scope of this article.

Conclusion

This article described a rational process, although imperfect, for form screening suitable for early development. It is viewed as an iterative process with screening activities becoming more comprehensive as more material and resources become available. Polymorph screening of the free form was recommended first provided it had the solubility and dissolution rate acceptable for early studies. Salt selection can be done either after the polymorph screen or concurrently if material is available. Cocrystal and amorphous screening are recommended if the salt and polymorph screens fail to find a suitable form. These screens can be conducted earlier if the API is incapable of forming a salt.

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Author Biography

Jeff Stults received his PhD in Organic Chemistry from the University of Wisconsin-Madison. He has worked in the chemical and pharmaceutical industries for almost 3 decades. His career in pharmaceutical solid state chemistry began about 12 years ago at SSCI, Inc., a contract research organization specializing in solid state chemistry. He is currently employed in the Small Molecule Pharmaceutics Group at Genentech, a Roche company, as a Senior Scientist specializing in solid state chemistry. His principal duties include polymorph screening, salt and cocrystal selection, crystallization, and preparation of amorphous materials including dispersions with an aim to deliver the appropriate developable form.