Reverse Engineering of Formulations Using X-ray Powder Diffraction Technology
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Techniques such as HPLC, LC-MS, FTIR and Raman are well suited to reverse engineer formulations of drug products.  X-ray Powder Diffraction (XRPD) technology is also a valuable complementary tool in reverse engineering of formulations. The combination of high resolution XRPD with both Rietveld calculation and Whole Powder Pattern Decomposition (WPPD) can be used for the quantification of the content of oral tablet formulations. A complicating factor in reverse engineering of formulations is that the Active Pharmaceutical Ingredient (API) is mixed with various excipients. Some commonly used excipients such as lactose monohydrate and sugars can be highly crystalline, whilst others such as stearic acid, magnesium stearate and talc are low crystalline. Just as the API, the excipients may also have different polymorphic (or pseudo-polymorphic) phases.  In addition, excipients can be amorphous or microcrystalline such as croscarmellose and microcrystalline cellulose.  To demonstrate the use of XRPD in reverse engineering of formulations we analyzed two tablet formulations of ibuprofen.  The results were collected using a combined Rietveld and WPPD approach and are outlined in Figure 1 and 2 below.

Figure 1. Analysis of a 200 mg ibuprofen tablet


Figure 1 outlines the result of an XRPD analysis of a 200 mg tablet from Farma B.V.  The product leaflet describes the composition as ibuprofen, stearic acid, corn starch, talk, titanium dioxide, starch, colloidal silicon dioxide, sodium starch glycolite and hydroxymethylpropylcellulose.

The coating of the tablet was removed and the inside content was crushed and analyzed by XRPD.  In Figure 1, the blue line is the obtained powder pattern, the red line is the calculated pattern and the grey line represents the difference between the blue and red lines.  The blue ‘sticks’ at the bottom of the graph show peak positions for ibuprofen and the black sticks plot positions for polymorph B of stearic acid.

Calculations demonstrated several phases in the tablet from which only two are crystalline.  These phases could be attributed to ibuprofen and polymorph B of stearic acid.  Quantification of the 3 phases gives 56.6±1% ibuprofen, 0.4±1% stearic acid form B and an amorphous part (43.0±2%).  No traces of talc or titanium dioxide were detected which means that they were either below detection limit or part of the coating.

Figure 2 outlines the result of an XRPD analysis of a 400 mg tablet from Marel B.V.  The product leaflet describes the composition as ibuprofen, magnesium stearate, talc, sucrose, titanium dioxide, calcium carbonate, pregelatinized starch, sodium croscarmellose, polyoxyl-35-castorolie, sodium benzoate and shellac.

Figure 2.  Analyze of 400 mg tablet of ibuprofen


Again, the coating of the tablet was removed and the inside crushed and analyzed by XRPD.  The blue line is the obtained powder pattern, red line the calculated pattern and the grey line represents the difference between them. The ‘sticks’ at the bottom show blue peak positions for talc, black positions for ibuprofen, green for sucrose and pink sticks for magnesium stearate.

The calculation showed that the tablet consists for 52±3% of an amorphous part and for 47±3% of a crystalline phase.  The ibuprofen content is 85.1±4% of the crystalline phase, the sucrose content 6.2±4%, the talc content 4.6±3% and the magnesium stearate content 4±2%.   Due of the lack of a crystal structure of magnesium stearate the cell parameters were used.

The obtained results reveal that the 400 mg tablet of ibuprofen comprises of 52±3% of amorphous material, 40.8±10% of ibuprofen, 3.0±10% of sucrose, 2.2±9% of talc and 2±1% of magnesium stearate.  No other crystalline (sodium benzoate, titanium dioxide and calcium carbonate) phases were detected meaning that content of these components are either below of detection limit or they are part of the coating of the tablet that was not examined.

The above analysis of the ibuprofen tablets demonstrates the benefit of using XRPD analysis in reverse engineering of formulations.  In particular, the crystalline phases can be calculated with acceptable quality. The analysis also gives confidence that in cases where the API is crystalline and more than one form exists of the API then these forms can be detected and quantified by XRPD analysis.