Kinetics of Transition of Anhydrous Carbamazepine to Carbamazepine Dihydrate in Aqueous Suspensions

doi:10.1002/jps.2600800519

Journal of Pharmaceutical Sciences

Volume 80, Issue 5, May 1991, Pages 496-500

https://doi.org/10.1002/jps.2600800519 Get rights and content

Abstract

When suspended in water, anhydrous carbamazepine (C₁₅H₁₂N₂0; 1) was transformed to carbamazepine dihydrate (C₁₅H₁₂N₂0 • 2H_zO; 2). Compound 1 was dispersed in water at 25 °C, and an aliquot of the slurry was taken at periodic intervals and immediately filtered under conditions which removed all the physically bound water from the solid. The weight fractions of 1 and 2 in the solid were quantified by two methods: (a) by determining the weight loss on drying the solid at 60 °C under reduced pressure to a constant weight and (b) by a quantitative powder X-ray diffraction technique. There was good agreement between the above two methods. More than 95% (w/w) of 1 was converted to 2 in 1 h and the decrease in the weight fraction of 1 with time was approximately a first-order process.

References (24)

M.M.J. Lowes et al.
Pharm. Sci.
(1987)
P. Kahela et al.
Int. J. Pharm.
(1983)
E. Laine et al.
Int. J. Pharm.
(1984)
J.B.J. Bogardus
Pharm. Sci.
(1983)
J.K.J. Haleblian
Pharm. Sci.
(1975)
E.A. Swinyard
In Remington's Pharmaceutical Sciences
(1983)
N. Kaneniwa et al.
Yakugaku Zasshi
(1984)
M. Kuhnert-Brandstatter
Thermomicroscopy in the Analysis of Pharmaceuticals
(1971)
H. Pohlmann et al.
Pharmazie
(1975)
T. Umeda et al.
Yakugaku Zasshi
(1984)

H. Kala et al.

Acta Pharm. Technol.

(1986)

C. Lefebvre et al.

Drug Dev. Ind. Pharm.

(1986)

Cited by (56)

Photoinstability in active pharmaceutical ingredients: Crystal engineering as a mitigating measure
2021, Journal of Photochemistry and Photobiology C: Photochemistry Reviews
Citation Excerpt :
Besides photoinstability, it has issues related to dissolution rates and phase transformations at high-temperature conditions. CBZ has several crystal forms―five polymorphs, several hydrates, and solvates―that differ in their physicochemical traits [144–146], particularly the extent and rate of photodegradation [143]. The colorimetric assessments ascertain that form II is less photostable than forms I and III.
Cocrystallization has evolved as an attractive prospect to broaden the chemical landscape of a drug entity, expand its therapeutic scope, and address physicochemical deficiencies of an active pharmaceutical ingredient (API). The non-covalent approaches to address the solubility and bioavailability of BCS Class-II and Class-IV drugs is an archetypal example and is a prolific topic. The present review highlights various supramolecular methods employed in addressing the photoinstability in drugs, emphasizing crystal engineering approaches. Because a greater proportion of the drugs are formulated in the solid-state, the structural factors—crystal packing, intermolecular interactions, packing density—remain a critical determinant in the observed extent of stability. Comprehending and amending these structural determinants using crystal engineering concepts proposes to address the photoinstability in drugs. Also, we highlight the pros and cons of the different adopted strategies in terms of formulation and the underlying challenges and put in prospect. The review provides a correlative assessment of the structure-property relations that could further augment the foundations of factual knowledge in drug stability.
Dissolution enhancement of carbamazepine using twin-screw melt granulation
2020, European Journal of Pharmaceutics and Biopharmaceutics
The current study explored the twin-screw melt granulation (TSMG) as a potential technology for the water solubility enhancement of biopharmaceutical classification system (BCS) class II drugs. As a model drug, carbamazepine (CBZ) was formulated with three different polymers as melt granules produced in a co-rotating twin-screw granulator. Polyethylene glycol 6000 (PEG 6000) and Kolliphor® (poloxamer) P407 were used as binding materials at two different granulation temperatures (T_max: 70 °C; 100 °C). Additionally, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) was chosen as binder of higher melting/ granulation temperature (T_max: 140 °C). Temperature dependent polymorphic transition of CBZ during melt granulation was observed and identified using XRPD- (X-ray powder diffraction) and FTIR- (Fourier transform infrared spectroscopy) analysis. The effects of polymer type, polymer content (10, 15, 20% (w/w)) and granulation temperature on polymorphic transition, their impact on wettability (contact angle via drop shape-analysis), and the resulting dissolution performance at non-sink conditions in phosphate buffer (pH 6.8), were studied. This study showed that TSMG led to a crystalline system facilitating supersaturation when brought in solution, even when high drug loads (up to 90% (w/w)) were used.
In general, for all granules produced, the supersaturation level and its duration varied with the extent of polymorphic transition and binder concentration. The results of this study indicated the importance of temperature control and polymer selection for tailoring desired dissolution profiles.
Full spectroscopic characterization of two crystal pseudopolymorphic forms of the antiandrogen cortexolone 17α-propionate for topic application
2017, Steroids
Citation Excerpt :
Recently, CP was characterized in solution by spectroscopic and theoretical techniques [9], but a detailed investigation of the structural origin of the pseudopolymorphism of this compound is still missing and this will be accessible only by elucidation of the internal arrangement of the molecule in the crystal lattice. For the solid 17α-propionate, it is reasonable to hypothesize the complete conversion to CPW when CP is suspended in water in the product formulations [12]. It is important to underline that different local dissolution and solubility rates could lead to remarkable bioavailability changes, thus affecting the efficacy and safety of the product, especially in long-term use.
Cortexolone-17α-propionate (CP) is a topically active antiandrogen useful in the treatment of skin disorders. In the solid state, three anhydrous forms of this drug (CPI, CPII and CPIII) occur, together with one hydrated crystal (CPW). The single crystal structure of the monohydrated phase, CPW, compared with that of the anhydrous form CPIII, shows a markedly different solid state behavior. These latter pseudopolymorphic forms have also been fully characterized by spectroscopic methods.
Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals
2017, Advanced Drug Delivery Reviews
Active pharmaceutical ingredients (APIs) may exist in various solid forms, which can lead to differences in the intermolecular interactions, affecting the internal energy and enthalpy, and the degree of disorder, affecting the entropy. Differences in solid forms often lead to differences in thermodynamic parameters and physicochemical properties for example solubility, dissolution rate, stability and mechanical properties of APIs and excipients. Hence, solid forms of APIs play a vital role in drug discovery and development in the context of optimization of bioavailability, filing intellectual property rights and developing suitable manufacturing methods. In this review, the fundamental characteristics and trends observed for pharmaceutical hydrates, solvates and amorphous forms are presented, with special emphasis, due to their relative abundance, on pharmaceutical hydrates with single and two-component (i.e. cocrystal) host molecules.
A new hydrate form of diflunisal precipitated from a microemulsion system
2013, Colloids and Surfaces B: Biointerfaces
Citation Excerpt :
The suspension of anhydrous metronidazole benzoate in water at a temperature lower than 38 °C leads to the formation of the metronidazole benzoate monohydrate [11]. Carbamazepine dihydrate could be obtained by suspending carbamazepine particles in water [12]. Hydrates can also be obtained from binary or mixed solvent systems.
Three microemulsion systems were applied as solvents for polymorph screening of seven active pharmaceutical ingredients (APIs): carbamazepine, piroxicam, sulfaguanidine, nitrofurantoin, theophylline, quercetin, and diflunisal. All the recrystallized compounds were examined by using powder X-ray diffractometry, differential scanning calorimetry, elemental analysis, Karl Fischer titration and dissolution rate. A new crystal form of diflunisal hydrate was discovered by the cooling method of recrystallization in a water-in-oil microemulsion system, composed of water, alkane and dioctyl sodium sulfosuccinate. The new hydrate form of diflunisal was characterized and confirmed to be a stoichiometry of diflunisal:water of 1:1. The other two microemulsion systems were able to convert the anhydrous diflunisal Form I to Form III. The dissolution rate of diflunisal hydrate is unexpectedly much higher than that of anhydrous ones (Forms I and III). All the other six APIs (carbamazepine, piroxicam, sulfaguanidine, nitrofurantoin, theophylline and quercetin) recrystallized from the microemulsion systems were all converted into hydrate form.
Solution-mediated phase transformation: Significance during dissolution and implications for bioavailability
2012, Journal of Pharmaceutical Sciences
Solubility improvement of poorly soluble drug compounds is a key approach to ensuring the successful development of many new drugs. Methods used to improve the solubility of drug compounds include forming a salt, cocrystal, or amorphous solid. These methods of improving solubility can often lead to a phenomenon called solution-mediated phase transformation, a phase change that is facilitated through exposure to solution. Solution-mediated phase transformation occurs in three steps: dissolution to create a supersaturated solution followed by nucleation of less soluble phase and the growth of that phase. When the growth of the less soluble phase occurs on the surface of the metastable solid, this phenomenon can cause a marked decrease in dissolution rate during in vitro dissolution evaluation, and ultimately in vivo. Therefore, transformation to a less soluble solid during dissolution is an important aspect to consider when evaluating approaches to increase the solubility of a poorly soluble drug. Identification of solution-mediated phase transformation during dissolution is reviewed for powder dissolution, rotating disk method, and channel flow-through apparatus. Types of solution-mediated phase transformation are described in this report, including those involving salts, polymorphs, amorphous solids, and cocrystals. Many experimental examples are provided. Evidence of potential solution-mediated phase transformation in vivo is discussed to better understand the relationship between in vitro dissolution evaluation and in vivo performance.

View all citing articles on Scopus

View full text

Article preview

Journal of Pharmaceutical Sciences

Abstract

References (24)

Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

Pharm. Sci.

Pharm. Sci.

In Remington's Pharmaceutical Sciences

Yakugaku Zasshi

Thermomicroscopy in the Analysis of Pharmaceuticals

Pharmazie

Yakugaku Zasshi

Acta Pharm. Technol.

Drug Dev. Ind. Pharm.

Cited by (56)

Photoinstability in active pharmaceutical ingredients: Crystal engineering as a mitigating measure

Dissolution enhancement of carbamazepine using twin-screw melt granulation

Full spectroscopic characterization of two crystal pseudopolymorphic forms of the antiandrogen cortexolone 17α-propionate for topic application

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals

A new hydrate form of diflunisal precipitated from a microemulsion system

Solution-mediated phase transformation: Significance during dissolution and implications for bioavailability