XRPD quantification of polymorph impurities in finished drug product

Introduction

At DANNALAB we are dedicated to characterisation of pharmaceutical substances. We normally use X-Ray scattering methods such as XRPD. Our main objective is to control the API state at different manufacturing steps. Beyond this we want to monitor the state of API within the finished drug products and to compare it with known specifications.

Scope

In the characterisation of finished drug products, quantification of low-level polymorph impurities becomes an analytical challenge. The reasons for this are related to the nature of finished drug products – which in many cases will be in solid dosage form.

Analytical procedure

The analytical procedure for quantification of polymorph impurities consists of the following steps:
- Selection of “marker” peaks or area within the pattern – “single peak” versus the “full pattern” approach
- Preparing the set of mixtures to recreate the different impurity contents
- Building the regression curve, statistics, and finally quantification of analyte

Challenges

- The selection of optimal marker peaks is different for each drug product
- The preparation of the mixtures is influenced by the shape and statistics of crystallites
- The stability of the analyte in mixtures may be an issue and often unknown
- The data from artificial mixtures may be not representative for the actual drug product due to the omission of technological steps

Characteristics to consider:

- Identification: Specificity, Accuracy, Precision
- Quantification: Repeatability, Linearity, Range, Quantification Limit (LOQ)

Test case 1: API - anhydrate form is converted to hydrate during the wet granulation

- Production steps: API > dry mix > blended granules > core tablets > coated tablets
- 100% conversion of API to hydrate is expected in blended granules obtained from the contact of dry mix with water
- Scope: the method to quantify an anhydrate level in finished tablets
- Problem: How to monitor anhydrate when it is not readily available after the contact with water?

Procedure

- Dry mixtures of different concentrations of dihydrate within hydrate + placebo matrix created and evaluated;
- The processing to dosage forms introduces some changes on the hydrates and anhydrate peaks intensities versus placebo
- Assumptions are made about the influence of tabletting on the intensities of both substances

Quantification

Regression curve of marker peak intensity as function of API anhydrate concentration (%).

Test case 2: Method for quantification of a small amount of API anhydrate in the hemihydrate

- A method to monitor minor traces of original API anhydrate in the hemihydrate is required;
- Full pattern approach for quantification;
- Three repetitive series of 0%, 2.5%, 5%, 7.5%, 100% concentrations;
- Analysis: full pattern auto-scaling program

Patterns at different % of anhydrate form: 0%,1.5%,3%,4.5%,6%,7.5%,100%(red).

Results

Linearity: Slope = 0.98%, Offset =-0.003%, R=0.9955
Precision: Sigma =0.2%; Detection limit (conservative): 0.66%; Quantification limit (conservative): 2%; Accuracy (relative, quantification): 5%; Range: 0% - 7.5%

Quantification of anhydrate content in hemihydrate.