Dissolution testing has a key role in the development and quality assurance of goods manufactured in oral solid dose form.This test is considered an important resource that helps assess the release properties of drugs.¹ Dissolution testing, in the pharmaceutical industry and regulatory compliance, is not only needed to ensure continued quality assurance as a routine procedure but also to make in vitro in-vivo correlations (IVIVC), especially of poorly soluble drugs. According to the Biopharmaceutics Classification System (BCS), ciprofibrate is classified as a BCS Class II compound, that is, low water-soluble and high permeability, which means that ciprofibrate dissolution is the rate-limiting process in its absorption and bioavailability. It is, hence, imperative to develop a powerful and differentiating dissolution mechanism over ciprofibrate in order to maintain a uniform drug release pattern and activity.²

Ciprofibrate (2-(4-(2,2-disgusting cyclopropyl) phenoxy)-2-methylpropanoic acid) is a hypolipidemic agent employed in the treatment of dyslipidemic state through reduction of the levels of LDL and VLDL, with a concomitant elevation of the levels of HDL cholesterol. It is useful in heart conditions and helps in preventing cardiovascular complications; therefore, making it necessary to have batch-to-batch consistency and performance of its tablet formulation by using validated dissolution tests.^3,4

Analytical validation of a dissolution procedure proves that the test system would always provide valid, precise, specific, and reproducible results under stated conditions and parameters.⁵ In the absence of validation, dissolution data can be unreliable, as it might fail to capture product variabilities that are of paramount importance during formulation or manufacturing and can directly affect drug performance.⁶ Due to the highly variable nature of dissolution testing, especially in poorly soluble drugs, it is essential to have a close control of the parameters in the test and a validation process as per regulation e.g. International Council on Harmonisation (ICH).⁷

Moreover, UV spectrophotometry is a less expensive and more dependable analysis tool used to measure ciprofibrate levels throughout the revelation processes.⁸ Scientifically valid dissolution procedure may be developed by confirming the various parameters, including linearity, accuracy, precision, and robustness of a dissolution method.⁹ The first aim of the proposed work is the development of the dissolution method of ciprofibrate tablets, as well as its analytical validation, which will satisfy the requirements of regular quality control and regulatory compliance.¹⁷ The validation procedure refers to the testing of key performance attributes so that the applicability of the particular process with respect to its use.^10,11 Setting up such a validated procedure is likely to help ensure the quality and consistency of ciprofibrate release from tablets, and to reliably evaluate this release throughout its shelf life, and hence, the therapy.¹²

The originality of this work could be described by the fact that a biorelevant and cost-effective method of dissolution has been successfully developed and analytically validated, which is specific to one poorly water-soluble BCS Class II drug, ciprofibrate.¹³ The developed work offers a system of a sustained-release tablet that was realized in a laboratory using adequate excipients and represents a foreseeable option to study the matter academically and industrially.¹⁴ The test is efficient enough to evaluate the solubility of ciprofibrate in different conditions, since it performs the experiment using several pH buffer systems that simulate physiological conditions.^2,3 A credible UV-spectrophotometric technique was developed for the dissolution test, entailing an easy but authentic analysis strategy that was inexpensive in contrast to other costly procedures (such as the HPLC). Moreover, the experimental procedure was also established in accordance with the Indian Pharmacopoeia and ICH; therefore, it could be relevant on a regulatory level too.^18,19 This study addresses an essential research deficiency on the elaboration of the dissolution methods of ciprofibrate and establishes the base of related future investigations of in vitro and in vivo correlation and ways to improve the bioavailability of the drug.^15,16

The active pharmaceutical ingredient (API) used in making the sustained-release tablet was ciprofibrate, which was obtained commercially and used in the laboratory. They were produced to have 100 mg of ciprofibrate per tablet, which was translates into 155 mg of sustained-release mixture. The manufacturing process consisted of the CIP API powder 100 mg combined with excipients according to the required exact amount to create ten tablets with a strength of 100 mg, based on the requirements provided in the Indian Pharmacopoeia (IP). The studyers prepared various media of dissolution; phosphate buffers (pH 6.4, 6.8 and 7.2), borrow ate buffer (pH 8.0), 0.1 zon hydrochloric acid and distilled water. As a solvent, methanol (A.R. grade), in which ciprofibrate was highly soluble, has been used. Other reagents used were HPLC-grade methanol, HPLC-grade acetonitrile, LR-grade methanol, and HPLC-grade water, which were prepared as recommended in the IP and pharmaceutical regulations.

Instruments used in the present work were a tablet compression machine (Rimek Mini Press) to produce tablets, a digital ultrasonic cleaner (sonicator bath), and a mechanical stirrer to select and homogenize the preparation of dissolution media. The absorbance and solubility were measured with a Shimadzu UV-1800 spectrophotometer, and the area under the pharmacokinetic concentration profile was determined with a Shimadzu LC-20AT high-performance liquid chromatography (HPLC) system. Other additional equipment was a Tempo Instruments hot air oven to dry the samples, a Shimadzu weighing balance, AUX-220 (Japan), which was used to make the correct measurements, and a pH meter to prepare the buffer. The quality control tests of tablets included mechanical strength and friability determination with the Monsanto hardness tester and USP Roche friabilator, respectively.

For the UV analysis of the CIP medication, a straightforward and dependable procedure was employed. The standard solution was created by combining 100 mg of the drug with 100 mL of AR-grade methanol to create a 1000 ugmL solution. From this solution, a 100 ugmL stock solution was created. The concentration of each aliquot of the medication solution was changed using the given values of 10–60 ug/mL for the corresponding pH buffer solutions. Analyzing and interpreting the test findings served to validate the method. The baseline was established using spectrometric measurements in the UV for each separate buffer solution based on its accuracy, precision, and linearity. The test was conducted using 0.1 N HCL, 6.8 phosphate, and 8.0 borate buffer solutions, with the use of a dissolution device. At first, the device was allowed to stabilize at a temperature of 37°C. Each ciprofibrate pill was submerged in a 900 mL vessel of the dissolution device before the dissolution test was conducted. The instrument’s stirring speed was regulated to 50, 75, and 100 rpm using the paddle device; 5 mL samples were taken at various time intervals, including 5, 15, 30, 45, 1–4 h, and 24 h. The samples were examined spectrophotometrically at 275 nm in the UV apparatus.

The solubility study revealed that Ciprofibrate exhibited pH-dependent solubility. In phosphate buffer (pH 6.8), the concentration was 0.3211 mg/mL with a Cs/Cd ratio of 1.938. In borate buffer (pH 8.0), the solubility increased to 1.0160 mg/mL with a Cs/Cd ratio of 5.871. The highest solubility was observed in 0.1 N HCl (pH 1.2), with a concentration of 1.0248 mg/mL and a Cs/Cd ratio of 15.736. These findings indicate that the drug is more soluble in acidic conditions compared to neutral or alkaline media (Table 1).

The stability study of ciprofibrate in various buffer systems over 48 h showed minimal degradation under most conditions. In phosphate buffers, a gradual decrease in concentration was observed, with pH 6.4 showing a 5.289% reduction at 24 h and 7.4932% at 48 h; pH 6.8 exhibited a larger difference of 7.86% at 24 h and 16.72% at 48 h; and pH 7.2 showed 9.982% and 10.802% differences at the respective time points. In phthalate buffer (pH 4.4), the changes were comparatively small, with 4.36% at 24 h and 7.976% at 48 h. Borate buffer (pH 8.0) demonstrated good stability, with differences of 1.897% and 2.572% at 24 and 48 h, respectively. The highest stability was observed in 0.1 N HCl, with only 2.032% and 2.632% differences over 24 and 48 h. Overall, ciprofibrate was most stable under acidic and alkaline conditions, with greater degradation occurring near neutral pH (Table 2 and Figure 1).

The linearity study for ciprofibrate demonstrated an excellent correlation between concentration and absorbance within the calibration range of 2–12 µg/mL. The regression equation was found to be y = 0.3224x – 0.0042, with a slope of 0.3224 ± 0.0069 and an intercept of 0.0042 ± 0.0034. The correlation coefficient (r) was 0.9997, indicating a highly linear relationship and confirming the method’s suitability for accurate quantification of ciprofibrate across the tested concentration range (Table 3).

The forced degradation study of ciprofibrate under different stress conditions revealed significant degradation in acidic, basic, oxidative, and photolytic environments, while no degradation was observed under normal conditions (methanol: water, ambient temperature). Acid hydrolysis with 1 N HCl resulted in 60.27% degradation after 3 h. Basic oxidation with 1 M NaOH showed the highest degradation, reaching 69.92% after 5 h. Oxidative stress using H₂O₂ led to 60.17% degradation in 3 h. Photolytic exposure for 2 h caused 54.37% degradation. Under normal storage conditions, the drug remained stable with no detectable degradation even after 24 h. These results indicate that ciprofibrate is highly susceptible to degradation under acidic, alkaline, oxidative, and light conditions but stable in neutral, ambient environments (Table 4).

The accuracy test resulted in high reproducibility of the ciprofibrate assay technique. Precision within a day was determined at 24, 48 and 72 h by six replicate determinations (n = 6 Determination of intraday precision: n = 6 tablets per time point). The average assay values were 101.67% − 0.77 RSD, 100.46% − 0.49 RSD, and 100.32% − 0.78 RSD, respectively, with all the values falling well within the acceptance criteria of 0.20 RSD, which is the acceptable assay methods. Interday accuracy that was measured over 3 days with n = 6/day gave an average of 101.20% + 0.98 RSD. All time points showed close overlap of the 95% confidence intervals with the label claim, which is also a positive indication of the reproducibility. One-way ANOVA (GraphPad Prism 10.0 software, GraphPad Software Inc., San Diego, CA, USA) was used to test intra- and interday variability, and no differences were found to be significant (p > 0.05). These findings show that the method is accurate, reproducible, and reliable in routine ciprofibrate analysis (Table 5).

The robustness study for ciprofibrate showed that deliberate small variations in analytical conditions did not significantly affect assay results, demonstrating the method's reliability. The mean ± RSD% values were 100.32 ± 0.97% and 99.87 ± 1.69% for the addition of 8 mL and 15 mL methanol, respectively. Sonication for 15 min and 25 min yielded results of 102.14 ± 0.32% and 102.41 ± 0.39%, respectively. Storage for 24 h at room temperature (25°C) resulted in 101.72 ± 0.46%, while analysis under regular conditions gave 100.01 ± 0.70%. These results confirm that the method is robust and unaffected by minor procedural changes ( Table 6).

The current study has shown and proved a new method of dissolution testing of ciprofibrate sustained-release tablets, which is relevant and reliable in the quality of pharmaceuticals. The manufacturing process was conducted under clean and controlled conditions, whereby it yielded reproducible, stable, and pharmacopoeia-compliant tablets, besides having satisfactory physical properties. An optimized excipient composition has been used to successfully produce sustained-release tablets containing 100 mg of ciprofibrate, with a final product of good mechanical strength and homogeneity. Dissolution experiments conducted in well-controlled experimental conditions and selected buffer media gave valid, repeatable, and discriminatory findings. This is especially relevant to ciprofibrate, which is the BCS Class II drug, and the rate-limiting process in its absorption is its dissolution. The required analytical approach, which was UV spectrophotometry, was found to be precise, accurate, and repeatable when analyzing ciprofibrate in various media. Its validation method proved it to be suitable in routine analysis, especially when used alongside suitable dissolution media, reflecting physiological pH conditions. Ciprofibrate appeared to be typically well-soluble at low and high pH values, but not in the neutral pH range, which highlights the necessity of biorelevant testing, including gastric conditions simulations.

This paper identifies the possibility of determining the best dissolution parameters and media of poorly soluble drugs to enhance the predictability of in vivo behavior. Future studies ought to be aimed at developing in vitro–in vivo correlations (IVIVC) and the use of biorelevant dissolution media, as well as alternative drug delivery approaches, including nanoparticle preparations or solid suspensions, to increase the bioavailability of ciprofibrate. Moreover, the combination of pharmacokinetic modeling and machine learning can further optimize dissolution testing procedures and can be used to facilitate the design of controlled drug delivery systems. The next procedures will involve the IVIVC calculations to determine the bioavailability of ciprofibrate more accurately and use the validated methodology in bioequivalence trials. In addition to ciprofibrate, this method can also be regarded as useful with the other BCS Class II medications, thus ushering in larger breakthroughs in the field of pharmaceutical formulation and analysis. The study would be able to be a strong dissolution method to ciprofibrate with major revisions to enhance the methodological rigor, address any inconsistencies, and improve clarity that could inform future IVIVC and formulation development initiatives.