Choosing the Best Solid Form for Successful Drug Development

One of the most important steps in early drug development is the selection of the appropriate solid form. Each solid form will have different properties. These properties will not only determine the stability and handleability of the active ingredient, but also its performance as a drug. Stability and hygroscopicity, for instance, will determine the shelf life of the drug, while its solubility will have a direct impact on the bioavailability of the active ingredient. The solid form will also impact how costly the drug is to produce on a large scale.??

Very broadly speaking, most people will be familiar with two forms of solids — crystalline and amorphous. Crystalline solids are defined by a highly structured three-dimensional arrangement of their molecules. In contrast, amorphous solids lack this ordered structure. Although these are typically more soluble, they are usually less stable than their crystalline counterparts. To make things more complicated, crystalline and amorphous are not two discrete states of the solid, but a continuous in which assumptions often must be made, and in which the presence of even a small amount of amorphous material in a sample can significantly alter the properties of the bulk.??

When referring to crystalline forms of a small molecule, these can be single component crystals, or multiple component crystals. These, at the same time, can be classified as neutral forms (hydrates, solvates and cocrystals) or charged species (salts). Salts and cocrystals only differ in whether there has been a transfer of a proton, or this remains bound to the acidic molecule. This difference grants them different regulatory treatment in certain markets, posing both as a challenge and as an opportunity.??

This commentary discusses how pharmaceutical companies decide on the suitability of a solid form for effective drug development.?

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1. Solid-State Characterization?

Solid state characterization looks at the physical properties of materials when they are in solid state. It helps us understand their thermal behavior, including melting point, crystallinity and hygroscopicity. In early stages it can also shed some light on the particle morphology and habit of the materials prepared to date, although considering the early processes will differ significantly from the later ones, aspects like particle size distribution (PSD) and other bulk properties are better investigated at the time of developing a final scale up process. These properties determine how materials perform, stay stable, and behave during processing.?

Understanding these properties help scientists predict the hurdles they are likely to encounter during development. It guides the design of active ingredients and sets quality standards.??

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Solubility and Dissolution Testing?

Nowadays, most new drug candidates display poor solubility and dissolution rate. This is the most recurrent issue related to solid state development, since the lack of solubility or the slow dissolution rate will determine the bioavailability and therapeutic effect of the drug.?

Solubility is the amount of drug that dissolves in a given solvent at a specific temperature. In the case of drugs, we are typically referring to solubility in biorelevant media. This is a critical property that affects the bioavailability and efficacy of the drug.??

When measuring solubility, it is important to understand the ionization profile of the drug, since this is going to travel through different pHs from administration to adsorption and excretion. Typically, weak bases will protonate in the stomach, but are likely to reach supersaturation in the guts and precipitate, thus making its adsorption more difficult.??

Dissolution rate is the speed at which a drug dissolves in a solvent, often simulating the gastrointestinal environment. This rate can affect the oral bioavailability of the drug. The dissolution rate is measured using dissolution testing apparatuses where the drug is exposed to a simulated biological fluid, and the amount dissolved over time is quantified.?

It is important to understand whether the adsorption of a drug candidate is limited by its thermodynamic solubility, in which case a change of solid form may alleviate the problem, or by its dissolution rate, in which case, a reduction on the particle size (or an increase on the surface area of the material) may improve its performance.?

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Stability Studies?

It is often advisable to develop the most stable form of a drug, thus ensuring consistency on its physical properties throughout the development and manufacturing processes. However, sometimes, the most stable form does not deliver the performance required for therapeutic effect. In these cases, a metastable form, or even amorphous material, can be chosen for development. In these cases, ensuring the physical and chemical stability of the drug candidates is particularly important. From the handling and storage of the materials to the control of the properties that may affect the drug’s performance, it is critical to establish the bounds of temperature and humidity in which the selected form remains unchanged.?

Thermal stability studies evaluate how a drug reacts to temperature changes. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are amongst the most common techniques used to evaluate the thermal stability of drug candidates.?

TGA analyses measures the changes in weight that a sample suffers upon heating. These changes in weight typically correspond to loss of volatiles (i.e. water or organic solvents), whether surface bound or from the crystal lattice, dissociation of a salt or cocrystal, or degradation. By changing the parameters in which the analyses are conducted, we can gain additional information regarding these events.?

In contrast, DSC experiments measure the enthalpy, positive or negative, of the events taking place. For instance, an exothermic event (positive change in enthalpy) indicates a transformation to a more stable species (i.e. crystallization of amorphous material or degradation), while an endothermic event is most likely associated to desolvation (or dehydration) or melting of the crystalline form.??

Solid-solid transitions can be either exothermic or endothermic events, and this will depend on whether the system that we are investigating is a monotropic or an enantiotropic system. In the first one, one crystalline form will always be more stable that the other, while in the latter the relative stability of a polymorphic pair will change upon crossing the transition temperature. Understanding this becomes key to effect control on the crystallization processes.?

Moisture sensitivity testing evaluates the stability of a drug under different humidity conditions. Hygroscopic drugs can absorb moisture from the air and degrade or change their physical properties. This is evaluated by exposing the drug to controlled humidity environments and analyzing its stability.?

Both dynamic vapor sorption (DVS) and static storage in different conditions of temperature and humidity help us understand the behavior of the different crystalline forms. It is important to pay especial attention to the design of the experiments (what is the starting humidity level? do we start with a desorption or an adsorption cycle? how many cycles do we perform? what is the minimum and maximum time that a sample will stay at each humidity level? how crystalline is the sample we are using? what is the surface area?), since this will determine the outcome of the analysis. The interpretation of these results must be done in the context in which the analysis was performed, since changing the method may lead to different results.??

Equally, there are different conditions to use when investigating the stability of a sample in the humidity chamber. Quite often, accelerated conditions are used (40°C/75%RH), but other conditions could be as important to establish the threshold of conditions in which the sample will remain stable.??

Analyses by XRPD and HPLC before and after conducting the experiments will help us establish both the physical and chemical stability of the different forms to the conditions investigated.?

Additionally, the chemical stability of the sample must also be investigated by subjecting the different solid forms to different stress conditions like light, oxidizing environment, temperature and pH changes to see the degradation products. These studies help determine the conditions in which the drug remains unaffected and does not degrade over time, and help establish the shelf life of the drug substance.?

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2. Solid Form Screening?

A phase-appropriate screening strategy involves aligning the methods with the drug development stage. Early-phase screening identifies the polymorphs and understands their properties. High-throughput screening methods can be used with minimal material, although these also present their challenges and pitfalls. Often, a medium throughput approach is the most effective since it allows us to cover a wide range of the research space, while enabling confirmation or disregard of initial hits, minimizing false positive and negatives. As development progresses, more detailed studies to select the best form for further development, or to strengthen the IP position will be carried out.??

In early-stage solid form screening, scientists assess the suitability of the current form to undergo the most immediate preclinical studies, i.e. tox and PK studies. If this is not suitable, a change to a salt may be appropriate, especially if the parent compound does not display the right attributes to undergo the preclinical studies. It is aimed at identifying one polymorph, salt or cocrystal that will allow the preclinical studies to be carried out. At this stage, the best solid form of an active pharmaceutical ingredient (API), whether a polymorph, salt or cocrystal, may or may not have been found yet, but this is of little relevance for the initial studies.?

Subsequently, when the compound has entered or is getting ready to enter clinical phases, a more thorough study to identify the solid form with the most appropriate properties to enhance the therapeutic effect of the drug will be required. These studies are aimed at identifying the best form for development, focusing on the properties that will enhance the chances of the candidate becoming a drug, such as solubility, hygroscopicity or stability. It is also important to anticipate all the crystalline forms likely to appear during development and manufacturing so we can predict the behavior and control the quality of the materials produced. This stage is critical to optimize the therapeutic efficacy of the drug, processing characteristics, and intellectual property (IP) status.?

Polymorph Screening?

A polymorph screen is aimed at identifying different crystalline forms (polymorphs or pseudo-polymorphs) of an API. Each polymorph has different properties, such as stability, solubility, dissolution rate and bioavailability, which can impact the drug’s efficacy and shelf life. Early identification helps mitigate risks and allows optimization of the drug formulation by selecting the best polymorph for large-scale production. Regulatory bodies require polymorph information for approval, so a thorough screening strategy is required. Patenting a unique polymorph can give you a competitive advantage. By understanding how the different crystalline forms relate to each other, you can establish the necessary controls to ensure consistency in the drug’s properties and manufacturability.?

Salt Screening?

The selection of an appropriate salt for an API provides an opportunity to alter its physicochemical properties and resultant biological characteristics. Salts are often used to modify aqueous solubility; however, the salt form selected will influence a range of other properties, such as: hygroscopicity, chemical stability, dissolution rate, crystallinity and physical stability. Discovery of developable salt forms can, therefore, be the subject of novel intellectual property.?

Cocrystal Screening?

Just like salts, cocrystals can help modify different properties of the parent API to enhance their performance or facilitate its production. But unlike salts, cocrystals do not require the ionization of the drug candidate. Typically, hydrogen-bond, Van der Waals forces, or p-p stack interactions are the forces that sustain the crystal structure.?

For weak ionizable species, the frontier between a salt and a cocrystal can be very subtle, since the existence or not of a proton transfer will determine the type of species we are dealing with. This may have repercussions as to the type of regulatory treatment each species is subjected to, depending on the market of application.?

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3. Manufacturability Assessment?

It would be rare to get a process suitable for scale up directly from the medicinal chemist. During discovery, medicinal chemists develop process that can be easily applied to the preparation of a large number of structurally related compounds. There is no drive to develop a high yielding process that produces highly crystalline material of a given polymorph. However, once the candidate has been selected, process chemists modify the original procedure to control the crystalline form and particle attributes, reduce the amount of solvent used, maximize the yield of the crystallization and improve the purity profile of the material.???

Scalability in drug development refers to the ability to consistently produce a drug in large quantities while maintaining its quality, efficacy, and safety. As well as using material of comparable quality to that used during the lab scale experiments, we need to take into consideration the kinetics of dissolution and crystallization. We may encounter, for instance, a process that works well in the lab, but on scale up, the starting material takes longer to dissolve, by which time, spontaneous nucleation may have started, thus leading to problems on the control of the crystalline form. Understanding the process and identifying the parameters that may have an impact on the kinetics of the process helps avoid surprises when transferring from lab to large-scale production.?

Equally important would be to either control the particle properties or implement the appropriate downstream processes to ensure the selected form is obtained with the optimal attributes to be processed and efficiently manufactured into the final dosage form, like tablets or capsules. Processability covers handling, flowability and compressibility. Poor flowability can cause inconsistent dosing and production issues, so tools like powder rheometry (measuring flow) and shear cell testing (assessing material response to stress) are used. Mechanical properties like hardness (resistance to breakage), friability (how easily it crumbles) and disintegration time (to allow for fast dissolution) must meet quality standards and remain unchanged during storage.?

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4. Conclusions?

Selecting the right solid form can make or break your new drug. Understanding its physical properties and selecting the right solid form is at the heart of early drug development.?

Solitek makes this complex journey simple. Our approach is tailored to each client’s needs and stage of development by offering high quality, stage appropriate solid state services, including solid state characterization, solid form screening, crystallization process development and early enabling formulation services, thus simplifying complexity, reducing risk and maximizing returns by focusing on what’s needed at each stage.??

For companies looking to bring new treatments to market, Solitek delivers unmatched expertise to tackle solid state problems, a partnership that complements your team and faster progression through development stages, thus saving time and money?

Ready to turn a solid state into an opportunity??