Early Solid Form Screening To Guide Drug Substance Through Drug Product Development

By Abhijeet S. Sinha, Manager, Solid Form Services (SFS), Lonza

Solid form screening encompasses the search, preparation, and characterization necessary to identify, isolate, and ensure confidence in the stability and downstream manufacturability of a lead form. In many ways, this process serves as the bridge between drug substance and drug product for new chemical entities. One major component is the identification of polymorphs, which are differently arranged molecules in the crystalline lattice with the same chemical structure. Early screening, selection, and isolation of a lead polymorph helps manufacturers avoid additional costs and delays down the road. Also, solid form screening of salts and cocrystals can provide a solubility enhancement strategy to improve bioavailability of poorly soluble drugs. Solid form screening is highly customizable based on the stage of a drug development cycle (Figure 1). In the following case study from one of Lonza’s SFS customers, the workflow required for polymorph characterization, lead form identification, and crystallization process design has been examined.

Figure 1. SFS throughout drug development

Brief Overview of Solid Forms

Polymorphs of drugs have different molecular arrangements in the crystalline lattice with the same chemical structure. Solvates or hydrates have solvent or water molecules trapped in the lattice. Enabled forms such as salts are ionic compounds, whereas cocrystals consist of two or more neutral components in a crystalline lattice. Amorphous forms lack long range order.

In the European Union, polymorphs, salts, and cocrystals are considered the same active ingredient and may be eligible for generic application. Whereas in the U.S., the Food and Drug Administration (FDA) considers salts a different active ingredient. Thus, there is justifiable confusion in understanding the differences between forms. When you change the solid form, it affects the properties and potentially the formulation of your drug product (Figure 2). Chemical stability, hygroscopicity, impurity profile and handling properties could all be dependent on form. Critically, changing the solid form changes the solubility, which may in turn affect bioavailability of the drug.

Figure 2. An overview of properties affected by form

In 1965, chemist Walter McCrone made popular the belief that the longer you study a substance the more polymorphs you are likely to find. So, finding different polymorphs is inevitable; but the key is identifying them early enough to develop the right form and save time and resources. Also, regulatory agencies require robust understanding of polymorphs and their physicochemical properties.

Solid Form Screening Workflow

In early development, solid form screening involves characterization of the available form and absorption risk assessment, which provides guidance on the right technology for drug product formulation. If a drug requires solubility enhancement, then a salt or cocrystal screen can be considered for drugs having ionizable functional groups or hydrogen bonding groups.

Figure 3. SFS workflows

In late-stage development, solid form work can be geared towards troubleshooting of a crystallization process or search for additional forms to strengthen IP. No matter the stage, the goal of SFS is to make sure we have a viable solid form that is stable, soluble, and meets regulatory compliance. There are three predominant workflows:

1. Polymorph screening > developability screening > nominate lead form
2. Salt or cocrystal screening > developability screening > nominate lead salt or cocrystal form
3. Build the base crystallization process > isolate the lead form

Some of the considerations for a polymorph screen include structure, functional groups, process-relevant solvents, and method of isolation. In-silico screening can aid in determining the propensity of a drug to form polymorphs. Also, formation of hydrates/solvates should be considered especially water activity range and solvent systems that are prone to forming solvates. High-throughput experiments followed by extensive characterization using a suite of analytical techniques helps in building a polymorphic landscape. This information can then be used to select the lead form of a drug.

Search for enabled forms such as salts and cocrystals is dependent on the drug having ionizable functional groups and/or hydrogen bonding groups for cocrystallization. Lead salt/cocrystal forms of a drug are nominated based on the identity of the new form (preferably not a hydrate or solvate), manufacturability (scalable process), stability (form and chemical), and solubility enhancement required for target drug product parameters. The final step is developing a baseline crystallization process to isolate the lead polymorph and/or salt/cocrystal. Different crystallization methods such as cooling, solvent/anti-solvent, seeded, and a combination of the above methods can be employed to reliably target the lead form in high yields and having optimum morphology and particle size.

At Lonza’s Bend, OR facilities, we utilize a range of powerful analytical tools to execute these workflows (Figure 4).

Figure 4. Tools to assist SFS workflows

Case Study: Polymorphs of a Late-Stage API

Appearance of polymorphs at a later stage of drug development can be costly and detrimental to meeting the accelerated timelines. In this case study, two polymorphs – Form 1 and Form 2 were observed during the registration batch campaign of an API. The client designated the following goals:

1. Characterize Form 2
2. Build a solid form landscape to ensure that all polymorphs have been identified
3. Determine the implications of form change
4. Design a robust scalable crystallization process for the nominated lead form

First, we conducted a small-scale polymorph screen by three methods and in multiple solvent systems. All obtained solids were analyzed by powder X-ray diffraction (PXRD) before (wet cake) and after oven-drying to look for new stable patterns. In this case, we observed three new stable patterns. These included Form 1, previously identified as the lead form by the client, Form 2, which was discovered serendipitously during the registration batch campaigns, and Form 3, newly identified during our polymorph screen.

Figure 5. PXRD Data for Forms 1, 2, and 3

All three forms of the API were scaled up and characterized comprehensively. In Figure 5, you see the PXRD data for the different polymorphs and the distinctive peak differences between the three forms. Next, we analyzed them by polarized light microscopy (Figure 6).

Figure 6. Polarized light microscopy of Forms 1, 2, and 3

Form 3 consisted of fiber-like long needles. Form 1 also formed needles but with a better aspect ratio than Form 3. Form 2 consisted of blocks or plates. Form 1 was a well-established polymorph of the API. Forms 2 and 3 were characterized comprehensively and established as true polymorphs of the API. It was observed that rapid crystallization processes favor Form 3, and this form was difficult to access without a rapid solvent/anti-solvent process. Also, competitive slurries of Form 3 with Forms 1 and 2 confirmed that Form 3 was a metastable polymorph of the API. So, we focused our efforts on Forms 1 and 2.

From the competitive slurry experiments between Forms 1 and 2 at multiple temperatures and characterization data, we built a hypothetical energy diagram for the polymorphs (Figure 7). Form 3 was the least stable, Form 1 the second least, and Form 2 was the thermodynamically stable form at ambient conditions.

Figure 7. Hypothetical energy diagram for Forms 1, 2, and 3

The thermodynamic relationship between the forms proved interesting (Figure 8). Form 3 was metastable at all temperatures and monotropically related to Forms 1 and 2. Forms 1 and 2 were enantiotropic polymorphs; where Form 2 was stable below 100°C and Form 1 was stable above 100°C. Based on this data, Form 2 was designated as the lead form of the API.

Figure 8. A breakdown of the thermodynamic relationship between Forms 1, 2, and 3
 

Figure 9. The implications of form change and solubility on Forms 1 and 2

Next, we considered the implications of form change on solubility in biorelevant media. Form 2 dissolved slower (10x) compared to Form 1 (Figure 9). When Form 2 was milled to reduce particle size, solubility was within 10% of Form 1. Thus, changing the form of the API changed the solubility in biorelevant media, but micronizing Form 2 led to nearly matched performance with Form 1.

We also considered the impact of form change on the crystallization process (Figure 10). During our competitive slurries in different solvent systems, we noticed a dependence on the solvent system for conversion. Form 2 slurries did not convert to Form 1 under ambient conditions; it was stable with no dependence on the solvent system. Form 1 converted to Form 2 in select solvents where the dielectric constant was greater than 30.

Figure 10. Implication of form change on crystallization

Next, we determined the metastable zone width (MSZW) curves for Form 2 in different solvent systems. Also, we examined the impact of seeding on controlling form and particle size distribution. Finally, we built the base crystallization process as shown in Figure 11. We dissolved drug in the selected solvent system and added milled seeds of Form 2. This was followed by stirring the suspension and adding the crystallizing anti-solvent in two lots to crystallize the desired Form 2 of the API in high yields. We accounted for the dependency of the forms on the solvent system as well as the rate of addition of anti-solvent to control form and particle size distribution. This base crystallization process was successfully transferred to plant for scaled-up manufacturing of the drug.

Figure 11. Base crystallization process for Form 2

Conclusion

Solid form screening is highly customizable based on the phase of the drug development life cycle, and collaborating with an expert solid form team will help accelerate your timelines and reduce costs. Not to mention, understanding the solid forms of your API will set you up for regulatory success. In this case study, Lonza’s SFS team collaborated with a drug sponsor to help select their lead form from three polymorphs and design a base crystallization process that met regulatory compliance and allowed for successful synthesis of the desired form of the drug at larger scale.