Summary
Amorphous formulations are used to enhance bioavailability of poorly water-soluble APIs. However, amorphous forms are thermodynamically unstable and may crystallize during processing or storage, posing significant risk for product performance.
This application note demonstrates development and validation of an XRPD method to quantify low levels of crystalline forms within amorphous API formulations. The study addressed a cholesterol-lowering drug where differential XRPD analysis detected unwanted crystallization during the granulation step. Even small amounts of crystalline API can initiate further recrystallization, making sensitive quantification essential.
Background & Challenge
Why Amorphous Formulations?
Advantages of ASDs:
- Enhanced solubility: Amorphous forms dissolve faster than crystals
- Higher bioavailability: Critical for BCS Class II/IV drugs
- Supersaturation: Achieve concentrations above crystalline solubility
- Commercial products: Sporanox®, Norvir®, Zelboraf®, Onmel®
The Crystallization Risk
- During manufacturing: Hot melt extrusion or spray drying stress
- During storage: Humidity and temperature can induce crystallization
- During dissolution: Supersaturated solutions may precipitate
- Impact: Loss of solubility advantage, dose variability, batch failure
Methods & Experimental Design
Sample Information
Drug product: Cholesterol-lowering formulation
API state (design): Amorphous
Problem detected: During granulation step, amorphous API partially converts to crystalline form
XRPD Measurement
Instrument Parameters
- X-ray sourceCu Kα
- InstrumentLaboratory XRPD at DANNALAB
- Angular Range0-40 deg 2θ
Method Development
Approach: Single-peak marker method using differential XRPD
Calibration: 7 concentration levels of crystalline API in amorphous formulation
Analysis: Peak deconvolution to extract integral intensities
Regression: Linear calibration curve built over concentration range
Results Example: Batch Testing
Batch A (Fresh)
< 1% crystalline
Below LOQ — Pass
Batch B (3 months, 25°C)
< 1% crystalline
Stable — Pass
Batch C (6 months, 40°C)
2.3 ± 0.3% crystalline
Within spec — Pass
Batch D (Failed control)
8.5% crystalline
Out of spec — Fail
Figure 1. XRPD patterns showing quantification of crystalline API content in amorphous solid dispersion formulation. Calibration samples at different crystalline levels (black, teal, red curves) enable precise quantification down to LOQ of 2% wt for stability and batch release testing.
Stability Insight
Batch C shows onset of crystallization under accelerated conditions (40°C/75% RH, 6 months) with 2.3% crystalline API detected. While still within specification, this indicates potential stability concern. Real-time stability monitoring recommended.
Conclusion
The quantification of crystalline content in amorphous API formulations is critical for stability and product quality. This application note demonstrates development and validation of XRPD quantification methods with LOQ of 2% wt, suitable for monitoring crystallization in amorphous solid dispersions and other formulations where the API is intended to remain amorphous.
Related Application Notes
Conference Poster
Download: Crystallinity Determination by XRD, NIRS, DSC (PDF)
Work performed in cooperation with industrial partner.