Develop Solid Form Control and Improve Your API Properties
Almost all APIs are crystallized at some stage in their preparation, and many are formulated into drug product as crystalline materials. Crystallization in chemistry is a common approach to enhance chemical purity, acheive chiral resolutuon, and improve the reaction yield. Traditionally, API crystallization processes were optimized primarily around reactor throughput and chemical yield. Unless problems were encountered in product recovery or downstream use, consistency of solid form was often ignored.It is now understood that a crystalline API needs to exhibit consistent physical properties when made at each stage of the development process (gram to multi-kilogram scales). In doing so, formulation-development problems are minimized and regulatory requirements are met. Triclinic is experienced in generation of crystallization methods, including the background information necessary to impart solid form control (polymorphic form, particle size, etc). crystallization in chemistry, Chiral Resolution, Chemical Purity.
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Crystallization method development is critical for:
Production of the desired solid form
In API development, the chosen solid form is selected from all available forms due to its properties (e.g. dissolution rate, bioavailability, stability, handling, or intellectual property). The crystallization process must be capable of selectively producing the desired form (e.g. polymorph, hydrate, solvate, non-crystalline materials) with high efficiency and polymorphic purity.
Triclinic has the ability to provide your solid-form API of choice in kilo-scale batches. The material is suitable for pre-clinical development including excipient compatibility testing. We are also able to work with your API manufacturer of choice in order to maintain control and consistency which is often lacking. Instead of repeated attempts at producing the selected form using random chemical processes and conditions, Triclinic identifies the nucleation event and develops a process to control it - leading to consistency and predictability lot-to-lot. Contact us for a comprehensive discussion on how we can aid your critical scale-up step as you progress into the development process.
Polymorphic and Chemical Purity
During API development the crystallization process mist be capable of selectively producing the desired form with high purity and efficiency. This often requires systematic variation of parameters to obtain an optimal procedure. Our lab is fully versed in crystallization method development, optimization, and trouble shooting.
Crystallization is often the most effective method to purify a chemical compound at industrial scale. An optimal crystallization process can minimize or eliminate process impurities and residual solvents as well.
Particle Size, Morphology, and Distribution
In active pharmaceutical ingredients, bioavailability and efficacy are often directly related to particle size. Crystal size distribution often has the greatest impact on the quality and effectiveness of the final product. Smaller particles are often desired for their enhanced solubility and dissolution characteristics. Additionally, crystal size and shape directly influence key manufacturing steps downstream from crystallization.
For example, filtration and drying performance are particularly susceptible to changes in these particle characteristics. Final crystal size and shape can also directly influence the quality of the drug product having an effect on compressability, flowability, and manufacturability
Finally, size, density, morphology, hydroscopicity, static behavior, flowability, distribution, and other particle properties can dramatically impact the quality of a final drug product. These properties may be controlled through an optimized crystallization process.
Chiral Resolution
Often, only one enantiomer or diasteromer of an API is biologically active or desirable for production. Therefore, isolation and scale up to separate the desired enantiomer from the racemic mixture is needed. To produce an API with desired chirality, chiral separation via crystallization is often more economical and straight-forward than chiral chromatography. Additionally, the traditional purity yield limits using conventional chiral separation methods can be exceeded using crystallization.
Much of Dr. Pat Stahly's career was spent in the area of chiral chemistry, predominantly in generation of enantiomerically pure materials. While asymmetric synthesis is being used commercially, diastereomeric salt crystallization remains the industrial workhorse for production of pure enantiomers. An understanding of solid-state chemistry is crucial for planning, developing, and troubleshooting crystallization-based resolution processes.Generation of the binary phase diagram of a racemic mixture, either experimentally or by calculation, is a critical first step in planning a resolution.
Triclinic can guide you through an understanding of the solid-state chemistry of racemates and enantiomers, collection of necessary background information, selection of the appropriate resolution method, and generation of a robust process.
Process Optimization and Efficiency
In the later stages of drug development when scale-up is required, crystallization process optimization can be used to improve yield, reduce costs, waste, and time, and improve environmental and regulatory risk.
Small changes in a crystallization process may lead to undesirable events such as agglomeration, form conversion, and alternative nucleation. In order to overcome these issues, varying relevant process parameters such as cooling, stirring, seeding, degredant addition, and water activity can be used to identify the critical factors that influence nucleation and the characteristics of the desired solid product. Systematic variation forms the basis for a robust crystallization process design.
On and off-line monitoring during the course of the crystallization optimization provides valuable insight into nucleation and growth of the crystals as well as the desired polymorphic form.
Manufacturing Support, Problem Solving, and Process Evaluation
Triclinic Labs has extensive experience in API solid-form control, nucleation, and scale up and can assist in identifying critical process parameters that are impacting the physical attributes of your drug substance. We have several API manufacturers that we have evaluated and work closely with and can make recommendations for potent and non-potent manufacturing.
We can assist with:
- Troubleshooting and Optimizing Process Issues
- OOS Investigations And Resolution
- Solid and Contaminant Testing
- Vendor Recommendations
- Validation, Transfer
