Different crystal forms of APIs may have different physical and chemical properties, which may affect the stability of preparations, the production process, dissolution rate and bioavailability of preparations, etc., which have effect on the safety and effectiveness of drugs. The crystallization status of the excipients (such as the crystallinity of MCC, the crystal form of the fatty matrix and its ratio) will also have effect on the performance of the final products (such as compressibility, controlled release performance). Therefore, it's important to study the possible impact of the crystal form of the Reference Listed Drugs (RLDs) on each stage of the drug's life cycle, ensuring the quality of generic drugs.
For different dosage forms, the focus of crystal form research is different:
- For solid dosage forms, semi-solid dosage forms, and suspensions: focus needs to be placed on the impact of crystal form on the drug substance and formulation process and stability, as well as the impact on formulation dissolution and bioavailability/bioequivalence.
- For liquid preparations(such as oral liquids, injections, etc.): should consider the possible impact of different crystal forms of raw materials on the preparation process.
Figure 1. API solid form classification. (Anna, K.; et al. 2018)
In general, the selection of crystal form of the manufactured generic drugs tends to choose the same crystal form as the RLDs. Therefore, determining the crystal form of the RLDs is of great significance to the research and development of chemical generic drugs, especially for the consistency evaluation research. If the crystal form is different from that of the RLDs, the quality of the drug may not be desired. Alfa Chemistry provides a complete RLDs crystal form research solution, and assists you in selecting and preparing the ideal crystal form of your generic drug through the accurate identification of the crystal form of raw materials and excipients.
Effect of Crystal Form on Drug Properties
- Impact on bioavailability/bioequivalence:
Different crystal forms may lead to differences in solubility and dissolution rate, which in turn affect the bioavailability/bioequivalence of the preparation. - Impact on preparation process:
Different crystal forms of APIs and excipient can exhibit different physical and mechanical properties, including hygroscopicity, particle shape and size, density, fluidity, and pressure resistance, which can affect the purification process of APIs and the production of preparations. - Crystal stability:
After drying, pulverizing, granulating, ball milling and tableting and other preparation process steps, the RLDs may undergo crystal transformation under the influence of environmental factors such as temperature, humidity and light. The conditions and degree of crystal transformation and whether it will affect the drug quality needs to be fully researched.
Figure 2. Pharmaceutical Co-Crystals. (Arun, K.; et al. 2018)
Our Crystal Form Study Workflow
Non-destructive profiling of the RLDs
Comprehensive analysis of the crystal form, distribution, morphology, and particle size of the APIs and excipients of RLDs.
Crystal form identification of raw materials
Alfa Chemistry supports a variety of technical tools to accurately identify the crystal form of APIs and excipients.
| Analysis Method | What We Offer |
| Single Crystal X-ray Diffraction (SXRD) | Determine the crystal configuration and molecular arrangement. Determine the crystal solvent or crystal water Confirm the bonding between the salt-forming drug bases and acid roots
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| Powder X-ray Diffraction (PXRD) | |
| Infrared Spectroscopy (IR) | |
| Raman Spectroscopy (Raman) | Determine whether there are crystal form differences by observing the peak shape, peak position and peak strength Crystal form identification, which is complementary to the IR method
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| Differential Scanning Calorimetry (DSC) | |
| Thermogravimetric Analysis (TGA) | Determine whether the crystalline substance contains crystalline solvent or crystalline water Determine the existence of sample sublimation, decomposition process, and magnitude
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| Capillary Melting Point Method (MP) | |
| Hot Stage Microscopy] (TPM) | |
| Polarization Microscopy (PM) | |
| Solid-state Nuclear Magnetic Resonance Spectroscopy (ssNMR) | |
PAT real-time detection
Quality control of the product in real-time during the analysis process, including crushing, drying, mixing, tableting and coating.
Process evaluation
Imaging comparison of the RLDs and the generic drugs.
References
- Anna, K.; et al. Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs. Pharmaceutics. 2018. 10(1): 18.
- Arun, K.; et al. A Review about Regulatory Status and Recent Patents of Pharmaceutical Co-Crystals. Advanced Pharmaceutical Bulletin. 2018. 8(3): 355-363.
