Dissolution rate of ciprofloxacin and its cocrystal with resorcinol

Ràfols, Clara; Fael, Hanan; Fuguet, Elisabet; Outhwaite, Breeze; Lee, Samuel; Ruiz, Rebeca

doi:10.5599/admet.6.1.497

Cited by 8 publications

(6 citation statements)

References 21 publications

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“…This dissolution rate behavior is similar to that observed in a preliminary study conducted for a Ciprofloxacin-resorcinol cocrystal [30]. In fact, both APIs belong to the same family, and they have similar structures and pK a values, so similar dissolution rate behavior was expected.…”

Section: Intrinsic Dissolution Rate Studysupporting

confidence: 86%

“…Compared to pH 2, the percentage of dissolved Norfloxacin after 30 min of dissolution is similar in the cocrystal tablet, whereas it falls to 71% in the API tablet. This behavior has been reported for some ionizable APIs-Ciprofloxacin, among others [30]-and can be explained by the change in pH at the tablet-solution interface (pH x=0 effect) [40]. When a large amount of API is dissolved, a saturated API solution is created only at the interface with the tablet surface.…”

Section: Intrinsic Dissolution Rate Studymentioning

confidence: 57%

“…In fact, some of us have studied this coformer in other crystal engineering studies [25,26], with the results demonstrating its remarkable ability to improve the stability of vitamin D 3 via cocrystallization [27]. Resorcinol has also been previously utilized to prepare cocrystals with agomelatine [28], curcumin [29], and Ciprofloxacin, a fluoroquinolone antibiotic similar to Norfloxacin [30].…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile

et al. 2021

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A new cocrystal of Norfloxacin, a poorly soluble fluoroquinolone antibiotic, has been synthetized by a solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. The new cocrystal exists in both anhydrous and monohydrate forms with the same (1:1) Norfloxacin/resorcinol stoichiometry. The solubility of Norfloxacin and the hydrated cocrystal were determined by the shake-flask method. While Norfloxacin has a solubility of 0.32 ± 0.02 mg/mL, the cocrystal has a solubility of 2.64 ± 0.39 mg/mL, approximately 10-fold higher. The dissolution rate was tested at four biorelevant pH levels of the gastrointestinal tract: 2.0, 4.0, 5.5, and 7.4. In a first set of comparative tests, the dissolution rate of Norfloxacin and the cocrystal was determined separately at each pH value. Both solid forms showed the highest dissolution rate at pH 2.0, where Norfloxacin is totally protonated. Then, the dissolution rate decreases as pH increases. In a second set of experiments, the dissolution of the cocrystal was evaluated by a unique dissolution test, in which the pH dynamically changed from 2.0 to 7.4, stepping 30 min at each of the four biorelevant pH values. Results were quite different in this case, since dissolution at pH 2 affects the behavior of Norfloxacin at the rest of the pH values.

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Section: Intrinsic Dissolution Rate Studysupporting

confidence: 86%

Section: Intrinsic Dissolution Rate Studymentioning

confidence: 57%

Section: Methodsmentioning

confidence: 99%

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Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile

et al. 2021

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“…In this case, solubilities of lamotrigine-methyl paraben, lamotrigine-nicotinamide and lamotrigine-nicotinamide (monohydrate) cocrystals at 1:1 ratios and that of the lamotrigine free base in water, all having pH of ~5.5, were, respectively, 0.21, 0.30, 0.23 and 0.28 mg/mL, indicating no significant difference in solubility due to cocrystal formation. In another study, Ràfols et al [ 21 ] compared dissolution rates of a zwitterionic compound, ciprofloxacin, and its cocrystal with resorcinol under different pH conditions and observed that the parent compound dissolved faster at pH 2, while the cocrystal had somewhat higher dissolution rates in the intermediate pH conditions of 4, 5 and 5.5. However, at the intestinal pH condition of 6.5, both ciprofloxacin and the cocrystal had much lower and essentially similar solubility and dissolution rates irrespective of whether the studies were conducted in buffer or fasted state simulated intestinal fluid (FaSSIF), indicating that there were no solubility and dissolution advantages of cocrystal formation under intestinal pH conditions.…”

Section: Introductionmentioning

confidence: 99%

Investigation of possible solubility and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution rates of ketoconazole and its cocrystals as functions of pH

2019

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Since there are conflicting reports in the literature on solubility and dissolution advantages of cocrystals over free forms, we systematically studied solubility and intrinsic dissolution rates of a weakly basic drug, ketoconazole, and its cocrystals with fumaric acid and succinic acid as functions of pH to determine what advantages cocrystals provide. pH-solubility profiles were determined in two different ways: one by lowering pH of ketoconazole aqueous suspensions using HCl, fumaric acid and succinic acid, and the other by adjusting pH of cocrystal suspensions using respective coformer acids or NaOH. Similar pH-solubility profiles were obtained whether free base or cocrystals were used as starting materials to determine solubility. With the addition of fumaric and succinic acids to aqueous suspensions of free base to lower pH, the maximum solubility (pHmax) was reached at pH ~3.5-4.0, below which the solubility decreased and cocrystals formed. The solubility, however, continued increasing when HCl was added to ketoconazole suspension as no cocrystal or salt was formed. During determination of cocrystal solubility, a conversion to free base was observed when pH was raised above pHmax. Thus, pH-solubility profiles of cocrystals resembled solubility profiles commonly encountered with salts. Above pHmax, both free base and cocrystal had similar solubility under identical pH conditions; the solubility of cocrystal was higher only if the pH differed. In contrast, intrinsic dissolution rates of cocrystals at pH>pHmax under identical bulk pH were much higher than that of free ketoconazole since cocrystals had lower microenvironmental pH at the dissolving surface, where the solubility was high. Thus, cocrystals of basic drugs can potentially provide higher dissolution rates under intestinal pH conditions.

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“…Moreover, ciprofloxaine hydrochloride has been classified as BCS class IV [ 30 ]. Several attempts for tackling CIP’s low aqueous solubility issue include salt formation [ 26 , 29 , 31 , 32 , 33 , 34 , 35 , 36 ] and amorphization [ 23 ] with less frequent cases of cocrystallization [ 36 , 37 , 38 , 39 , 40 , 41 ]. As an example, Martinez-Alejo et al studied the cocrystal of ciprofloxacin and moxifloxacin hydrochloride salts with 4-hydroxybenzoic acid as coformer.…”

Section: Introductionmentioning

confidence: 99%

Formation of Ciprofloxacin–Isonicotinic Acid Cocrystal Using Mechanochemical Synthesis Routes—An Investigation into Critical Process Parameters

et al. 2022

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The mechanochemical synthesis of cocrystals has been introduced as a promising approach of formulating poorly water-soluble active pharmaceutical ingredients (APIs). In this study, hot-melt extrusion (HME) as a continuous process and grinding and ball milling as batch processes were employed to explore the feasibility of cocrystallization. Ciprofloxacin (CIP) and isonicotinic acid (INCA) were selected as the model API and coformer. CIP–INCA cocrystal was produced in all techniques. It was revealed that higher cocrystal content could be achieved at longer durations of grinding and ball milling. However, milling for more than 10 min led to increased co-amorphous content instead of cocrystal. A design of experiment (DoE) approach was used for deciphering the complex correlation of screw configuration, screw speed, and temperature as HME process parameters and their respective effect on final relative cocrystal yield. Statistical analysis showed that screw configuration, temperature, and their interaction were the most critical factors affecting cocrystallization. Interestingly, screw speed had minimal impact on the relative cocrystallization yield. Cocrystallization led to increased dissolution rate of CIP in phosphate buffer up to 2.5-fold. Overall, this study shed a light on the potential of mechanochemical synthesis techniques with special focus on HME as a continuous process for producing cocrystals.

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Dissolution rate of ciprofloxacin and its cocrystal with resorcinol

Abstract: Abstract

Cited by 8 publications

References 21 publications

Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile

Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile

Investigation of possible solubility and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution rates of ketoconazole and its cocrystals as functions of pH

Formation of Ciprofloxacin–Isonicotinic Acid Cocrystal Using Mechanochemical Synthesis Routes—An Investigation into Critical Process Parameters

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