Polymorphic formulation: Chemometric tablet assessment

Skip to Navigation

Ezine

  • Published: Dec 15, 2017
  • Author: David Bradley
  • Channels: Chemometrics & Informatics
thumbnail image: Polymorphic formulation: Chemometric tablet assessment

Painful painkiller

Chemometrics coupled to mid (MIR) and near (NIR) infrared spectroscopy, digital optical microscopy, differential scanning calorimetry, melting point, and dissolution properties have been used to predict the dissolution performance of different polymorphs in tablets of the widely used non-steroidal anti-inflammatory drug mefenamic acid.

Chemometrics coupled to mid (MIR) and near (NIR) infrared spectroscopy, digital optical microscopy, differential scanning calorimetry, melting point, and dissolution properties have been used to predict the dissolution performance of different polymorphs in tablets of the widely used non-steroidal anti-inflammatory drug mefenamic acid.

Mefenamic acid, s 2-(2,3-dimethylphenyl) aminobenzoic acid, is an anthranilic acid derivative, a so-called fenamate, type of NSAID. It is often prescribed for mild to moderate pain, in particular menstrual pain and also migraines associated with menstruation. It is not widely used in the USA because it is relatively expensive when compared to other NSAIDs, despite it now being off patent. Moreover, its side effect profile is incompatible with prescribing considerations for many physicians. For instance, mefenamic acid can cause headaches, anxiety, and vomiting, and in more serious case diarrhoea, vomiting blood, blood in urine, blurred vision, skin rash, itching, and swelling, sore throat and fever, and in extreme cases acute liver damage.

A new format

All that said, there are reasons to pursue this potent drug and to find better formulations of mefenamic acid tablets. It exists in four possible crystal forms, or polymorphs. The first two, Form I and Form II are the only two that have been isolated as pure crystals and characterized by a whole raft of techniques. Marina Antonio of the Universidad Nacional de Rosario, in Rosario, Argentina, and colleague Rubén Maggio, hoped to develop quantitative models to assess Form I in formulated products. As such, they have used to sets of samples, one to train and one to validate, a model based on mixing both polymorphs and an excipient to simulate commercial tablets. Sieving allowed them to homogenize particle size and samples were mixed mechanically. They also applied the same to a batch of commercial tablets.

For each sample, the team explains that they obtained full MIR and NIR spectra. The data were and used as the input for a partial least squares (PLS) algorithm separately. They add that optimization and internal validation were carried out using a "leave one out" procedure. "Full spectra and five PLS-factors were used for MIR; while, five 5 PLS-factors and mean centre spectra of full spectra were the optimal conditions for NIR," the team reports in the Journal of Pharmaceutical and Biomedical Analysis. "Accuracy and precision were assessed by evaluation of the actual versus predicted curve of validation set and by calculating validation set recoveries and deviations," they add.

Spectral model

The team reports that only NIR-PLS gave them adequate results and low deviations with the evaluation of commercial samples. The saw the same behaviour with their analyses of "spiked" tablets. Nevertheless, they were able to derive a multiple linear regression (MLR) model using dissolution profiles and Form I content that correlated dissolution with polymorphic richness. "This approach, coupled to previously developed NIR-PLS, may act as a valid tool to estimate dissolution profiles from solid forms," the team concludes."

While the pharmaceutical industry commonly looks for novel polymorphs of drugs with a view to clawing back an off-patent compound with a new form, the deeper meaning of better understanding polymorphic forms is their therapeutic profile. Absorption and bioavailability are critical to activity but can also be reflected in different side effects.

Related Links

J Pharm Biomed Anal 2017, 28, 603-611: "Assessment of mefenamic acid polymorphs in commercial tablets using chemometric coupled to MIR and NIR spectroscopies. Prediction of dissolution performance"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

Follow us on Twitter!

Social Links

Share This Links

Bookmark and Share

Microsites

Suppliers Selection
Societies Selection

Banner Ad

Click here to see
all job opportunities

Copyright Information

Interested in separation science? Visit our sister site separationsNOW.com

Copyright © 2018 John Wiley & Sons, Inc. All Rights Reserved