Drug–Drug Compatibility Evaluation of Sulfasalazine and Folic Acid for Fixed-Dose Combination Development Using Various Analytical Tools

The simultaneous administration of sulfasalazine and folic acid is regular practice in the therapy of inflammatory bowel diseases in order to maintain sufficient folate concentration in patients. Having multiple drugs in the therapy increases the possibility of patients failing adherence, thus unintentionally endangering their health. A fixed-dose combination of sulfasalazine and folic would simplify the classical polytherapeutic approach; however, the physicochemical compatibility investigation of two active pharmaceutical ingredients plays an important role in the development of such a product. In this work, various analytical tools were used to determine the physicochemical compatibility of sulfasalazine and folic acid. For the evaluation of chemical compatibility, infrared spectroscopy in combination with advanced statistical methods, such as the principal component analysis and cluster analysis, were used, whilst a simultaneous thermogravimetry/differential thermal analysis gave us an insight into the physical compatibility of two drugs. Isothermal stress testing, forced degradation and dissolution studies, followed by the analysis with a developed chromatographic method for the monitoring of folic acid, sulfasalazine and two of its related impurities, sulfapyridine and salicylic acid, gave us an insight into its chemical compatibility. The combination of the results obtained from the used techniques implies a satisfactory physicochemical compatibility between sulfasalazine and folic acid, which opens the path to the development of the proposed fixed-dose combination.

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A Comprehensive Approach to Compatibility Testing Using Chromatographic, Thermal and Spectroscopic Techniques: Evaluation of Potential for a Monolayer Fixed-Dose Combination of 6-Mercaptopurine and Folic Acid

Pharmaceuticals ◽

10.3390/ph14030274 ◽

2021 ◽

Vol 14 (3) ◽

pp. 274

Author(s):

Edvin Brusač ◽

Mario-Livio Jeličić ◽

Matija Cvetnić ◽

Daniela Amidžić Klarić ◽

Biljana Nigović ◽

...

Keyword(s):

Folic Acid ◽

Development Strategy ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Forced Degradation ◽

Spectroscopic Techniques ◽

Scanning Calorimetry ◽

Forced Degradation Studies ◽

Dose Combination ◽

Inflammatory Bowel

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.

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Isolation, Identification and Characterization of Degradation Impurity of Atorvastatin in Fixed Dose Combination of Atorvastatin and Ezetimibe

International Journal of Pharmaceutical Sciences and Drug Research ◽

10.25004/ijpsdr.2019.110506 ◽

2019 ◽

Vol 11 (05) ◽

Author(s):

Rajesh Desai ◽

Suresh Koradia

Keyword(s):

Reversed Phase ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Forced Degradation ◽

Preparative Hplc ◽

Atorvastatin Calcium ◽

Isolation And Characterization ◽

Dose Combination ◽

Liquid Chromatographic

The objective of this study is to isolation and characterization of unknown degradation product of Atorvastatin calcium in combination formulation product with Ezetimibe by using modern techniques of separation and aracterization. An unknown impurity is generating during a forced degradation study of Atorvastatin and Ezetimibe fixed-dose combination tablets. By using the gradient reversed-phase high-pressure liquid chromatographic method, unknown degradation impurity was detected and quantified in the range of 0.05% to 0.2% of Atorvastatin. The impurity was enriched by extreme oxidation degradation of Atorvastatin and isolated through preparative HPLC. The structure of the impurity was characterized by mass and NMR spectrum.

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Molecular insight into atypical instability behavior of fixed-dose combination containing amlodipine besylate and losartan potassium

Journal of Pharmaceutical and Biomedical Analysis ◽

10.1016/j.jpba.2016.12.035 ◽

2017 ◽

Vol 136 ◽

pp. 66-80 ◽

Cited By ~ 3

Author(s):

Tarun Handa ◽

Shalu Jhajra ◽

Shweta Bhagat ◽

P.V. Bharatam ◽

Asit K. Chakraborti ◽

...

Keyword(s):

Fixed Dose Combination ◽

Losartan Potassium ◽

Fixed Dose ◽

Amlodipine Besylate ◽

Dose Combination ◽

Insight Into

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Post-Marketing Surveillance of Fixed Dose Combination of Methylcobalamin, Alpha Lipoic Acid, Folic Acid, Biotin, Benfotiamine & Vitamin B6-Nutripathy for the Management of Peripheral Neuropathy

Journal of Diabetes Mellitus ◽

10.4236/jdm.2014.42019 ◽

2014 ◽

Vol 04 (02) ◽

pp. 124-132 ◽

Cited By ~ 4

Author(s):

Manish Maladkar ◽

Chitra Tekchandani ◽

Urja Dave

Keyword(s):

Folic Acid ◽

Peripheral Neuropathy ◽

Lipoic Acid ◽

Vitamin B6 ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Alpha Lipoic Acid ◽

Post Marketing Surveillance ◽

Post Marketing ◽

Dose Combination

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Development of a HPLC-DAD stability-indicating method and compatibility study of azathioprine and folic acid as a prerequisite for a monolayer fixed-dose combination

Analytical Methods ◽

10.1039/d1ay00294e ◽

2021 ◽

Vol 13 (11) ◽

pp. 1422-1431

Author(s):

Edvin Brusač ◽

Mario-Livio Jeličić ◽

Daniela Amidžić Klarić ◽

Biljana Nigović ◽

Sabina Keser ◽

...

Keyword(s):

Folic Acid ◽

Process Control ◽

Quality Assessment ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Compatibility Study ◽

Stability Indicating ◽

Stability Indicating Method ◽

Dose Combination ◽

Active Substances

Physicochemical compatibility of active substances confirmed using multiple techniques and a stability-indicating method developed for quality assessment and in-process control.

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