In the pharmaceutical industry, the development of a new drug is a long and meticulous process that requires critical decisions at every stage. One of the fundamental pillars, though sometimes overlooked, is the selection of the solid form of the active ingredient. This choice not only affects the efficacy and safety of the drug but also its stability, bioavailability, and ease of manufacturing. In this article, we will explore in detail the process of screening and selecting solid forms, its relevance in optimizing drug development, and how this approach can make a difference in bringing innovative medicines to market.
Introduction: Why Are Solid Forms Key in Drug Development?
The vast majority of drugs are presented as solids, such as tablets, capsules, or powders for suspension. However, the same molecule can adopt different solid forms, each with unique physical. These forms include:
- Polymorphs: Variations in the crystalline arrangement of a molecule.
- Salts: Products of the interaction between an acid and a base.
- Co-crystals: Structures that combine two or more neutral molecular components in a crystalline lattice.
- Amorphous forms: Non-crystalline states with a disordered molecular arrangement.
These differences directly influence critical characteristics such as solubility, thermal and chemical stability, bioavailability, and processability. For example, a poorly soluble solid form can limit the drug’s absorption in the body, while an unstable form might degrade before reaching the patient. Therefore, identifying and selecting the most appropriate solid form is an essential step to ensure the quality of the final product and optimize the entire development process.
What Does Solid Form Screening Entail?
Solid form screening is a systematic process aimed at identifying and characterizing all possible solid forms of a pharmaceutical compound. This procedure is typically carried out in the early stages of development, during the preclinical phase, with the primary goal of discovering the solid form that best suits the needs of the drug.
Screening Process
Screening begins with the generation of different solid forms using controlled crystallization techniques. Some of the most common methods include:
1. Cooling Crystallization Gradual reduction of temperature to induce crystal formation
This method involves gradually lowering the temperature of the solution containing the compound to be crystallized, so that solubility decreases in a controlled manner. The time required for this crystallization can range from hours to days, depending on the cooling rate and batch size.
Advantages and effects on the solid form:
- Being a relatively slow process, it promotes the formation of well-defined crystals and increases the likelihood of obtaining the thermodynamically most stable polymorphic form.
- However, if the cooling gradient is adjusted to be faster (minutes), metastable forms or smaller particle sizes may emerge.
Time scale: Typically, it falls within the range of hours or days, but it can be combined with other variables (such as seed addition or supersaturation control) to speed up or slow down the process.
2. Evaporative Crystallization
Slow removal of the solvent to promote nucleation. In this method, the solution is maintained at a controlled temperature or pressure while the solvent evaporates gradually, causing the solute to reach a state of supersaturation and precipitate as crystals.
Advantages and effects on the solid form:
- It allows slow and uniform crystal growth, typically associated with the stable form if the process extends over days or even weeks.
- When evaporation is faster (e.g., at reduced pressure or elevated temperatures), metastable phases or less stable polymorphs may appear.
Time scale: It usually spans from a few hours to several days. Prolonged processes (several days) typically result in larger, more stable crystals.
3. Use of Various Solvents
Exploration of conditions with organic or aqueous solvents
The physical and chemical properties of each solvent (polarity, dielectric constant, viscosity, etc.) influence the resulting solid form. In practice, a wide range of solvents (aqueous, organic, or mixed) is investigated to cover different nucleation and crystal growth pathways.
Advantages and effects on the solid form:
- By changing the solvent, hydrogen bonding interactions can be promoted or inhibited, solubility and supersaturation rates can be modified, thus opening possibilities for obtaining different polymorphs, solvates, or co-crystals.
- There is also the possibility of generating hydrates or mixed solvates that lead to forms with different physicochemical properties.
Time scale: Highly variable. Depending on the solvent’s nature and the specific technique (cooling, evaporation, antisolvent diffusion, etc.), the entire process can range from minutes (e.g., a sudden “quench” or cooling) to days or weeks (slow evaporation).
4. Crystallization under Variable Conditions
Changes in humidity, pressure, or temperature
This category includes various processes that modify not only temperature but also relative humidity (e.g., crystals forming under wet or dry atmospheres), pressure (e.g., using supercritical CO₂), or thermal cycles.
Key methods and examples:
- Ripening/Slurrying (months/days): A solid is kept in suspension (slurry) or left to “age” for an extended period, promoting conversion to the stable form.
- Spray-drying (seconds/minutes): A very rapid method to obtain fine powders; it often leads to amorphous or metastable forms due to the abrupt removal of the solvent.
- Grinding/compression (seconds): The application of mechanical forces can induce phase transitions (e.g., from stable to metastable or amorphous forms).
- Sublimation/lyophilization (minutes/hours): These remove the solvent (water or organic) at low pressures, potentially generating unique polymorphs or metastable phases, as the process occurs with little time for structural reorganization.
- Salting out/pH change (minutes): Rapidly altering the ionic strength or pH of the solution induces fast nucleation, often associated with the formation of salts or metastable crystals.
Time scale: Ranges from months (e.g., prolonged slurrying or storage at different humidities to transform the solid form) to seconds (e.g., sudden compression or thermal “quench”). Slower methods promote the stable form; faster methods typically generate metastable or transient polymorphs.
After generating these forms, they are characterized using advanced analytical tools, such as:
- X-ray diffraction (XRD): Determines the crystalline structure of polymorphs.
- Differential scanning calorimetry (DSC): Evaluates thermal stability and phase transitions.
Raman or infrared spectroscopy: Identifies molecular differences. - Thermogravimetric analysis (TGA): Measures changes in mass as a function of temperature to assess composition, solvent content, and degradation behavior.
- Dynamic vapor sorption (DVS): Analyzes moisture uptake and provides insights on the hygroscopicity and stability of the solid forms under varying humidity conditions
- Solubility analysis: Measures behavior in aqueous or biological media.
The result is a detailed “map” of the compound’s solid forms, which serves as the basis for subsequent selection.
Selecting the Optimal Solid Form: Key Criteria
With the information obtained from screening, the next step is to choose the most suitable solid form for the drug’s development. This decision is based on a rigorous evaluation of several factors:
- Solubility and bioavailability: The form must allow for effective absorption in the body. For example, amorphous forms are often more soluble than crystalline polymorphs but may be less stable.
- Stability: It is essential that the selected form withstands storage and manufacturing conditions without transforming into a less desirable form.
- Processability: Properties such as compressibility or flowability determine whether the solid form is viable for large-scale production.
- Intellectual property considerations: A novel solid form may be patentable, offering competitive advantages.
- Regulatory compliance: The form must align with the requirements of agencies such as the FDA or EMA.
In many cases, selection involves balancing advantages and disadvantages. For instance, a highly soluble but unstable form might require formulation adjustments to ensure its viability.
Advanced Techniques in Screening and Selection
Technology has transformed the way solid form screening and selection are approached. Some notable innovations include:
- High-throughput screening (HTS): Automated platforms that evaluate hundreds of crystallization conditions in parallel, speeding up the process.
- Computational modelling: Crystal structure prediction (CSP) algorithms anticipate possible solid forms based on molecular structure and help establish the relative stability of the known forms.
- Artificial intelligence: Data analysis with machine learning identifies patterns and predicts properties, optimizing decision-making.
These tools not only increase efficiency but also enhance the ability to discover innovative solid forms.
Real-World Cases: Lessons from the Industry
Inadequate selection of a solid form can have significant consequences. A classic example is ritonavir, an antiviral for HIV. After its launch in 1996, a more stable but less soluble polymorph was discovered, causing formulation problems and forcing a temporary withdrawal of the product. This case highlighted the need for thorough screening.
On the other hand, paracetamol (acetaminophen) illustrates how different solid forms serve different purposes. Form I, stable and common, contrasts with Form II, which offers better compressibility for tablets, demonstrating the versatility of this approach.
Regulatory Framework
Regulatory agencies, such as the FDA and EMA, require a complete characterization of the selected solid form. For example, the ICH Q6A guideline states that manufacturers must:
- Identify all possible solid forms.
- Justify the choice of the final form.
- Demonstrate stability and reproducibility.
Compliance with these standards is key to drug approval.
Benefits of Optimizing This Process
A rigorous approach to solid form screening and selection offers clear advantages:
- Improved efficacy: An optimized solid form maximizes bioavailability.
- Risk reduction: Avoids issues such as unexpected transformations.
- Accelerated development: Advanced techniques save time and resources.
- Competitive advantage: New forms can be patented, extending exclusivity.
Conclusion
Solid form screening and selection is not a mere formality but a strategic stage that defines a drug’s success. At Solitek, we are committed to leading this field, offering comprehensive solutions that optimize pharmaceutical development. With highly trained experts and cutting-edge technology, we help our clients turn challenges into opportunities, bringing more effective and safer medicines to market.
