Abstract
In this work, a systematical compatibility investigation of 6-mercaptopurine and folic acid, two commonly used medications in the treatment of inflammatory bowel disease, for the needs of a fixed-dose combination development strategy is shown. Various techniques and approaches, such as differential scanning calorimetry, isothermal stress testing, attenuated total reflectance–Fourier-transform infrared spectroscopy, dissolution medium stability and forced degradation studies, were used to elucidate the possible interactions from different aspects. The results predominantly point to the absence of physicochemical interactions between the examined substances in a variety of possible conditions. However, the forced degradation of the blend of substances and excipients in basic conditions showed a drastic degradation of 6-mercaptopurine, signifying that attention needs to be directed to the careful selection of the excipients for the formulation. To sum up, our findings indicate that a fixed-dose combination of 6-mercaptopurine and folic acid could be produced using one formulation blend, immensely simplifying its manufacture.
Highlights
The prevalence of inflammatory bowel disease (IBD), a chronic inflammatory condition affecting the gastrointestinal tract and joints, eyes, liver and skin [1], is on the rise in today’s society, mostly owing to a growing population and increasing life expectancy [2]
Since differential scanning calorimetry (DSC) is a rapid screening technique, it is commonly used in the initial assessment of drug–drug and drug–excipient compatibility [14]. 6MP and folic acid (FA) were analyzed separately and in 1:1, 2:1, 5:1 and 10:1 ratios
PABGA was present in the majority of the stressed samples, followed by HX, while pteroic acid (PA) was found in the solution thermal stress. p-aminobenzoic acid (pABA) was not observed in any of the tests
Summary
The prevalence of inflammatory bowel disease (IBD), a chronic inflammatory condition affecting the gastrointestinal tract and joints, eyes, liver and skin [1], is on the rise in today’s society, mostly owing to a growing population and increasing life expectancy [2]. Genetic factors play a large role in the pathogenesis, environmental factors such as smoking, diet, occupational lifestyle, gut microbiota and stress can initiate and modulate the disease’s progression [4] As this is an inflammatory condition mediated by the immune system, anti-inflammatory aminosalicylates, as well as immunosuppressants such as corticosteroids, thiopurines and monoclonal antibodies, are used in therapy. Folic acid (FA) deficiency is important, caused by either malabsorption or inadequate dietary intake Deficiencies of this vitamin are known to primarily cause macrocytic anemia, as well as birth defects in pregnant women, but some studies have pointed to a possible association between insufficient FA intake and the progression of dementia and Alzheimer’s disease [5], schizophrenia [6] and the progression and invasiveness of gastric cancer [7]. A recent meta-analysis of serum folate and B12 levels
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