The present investigation was aimed at using quality by design approach optimization of cocrystal preparation. The challenge was too many factors affect the final purity and yield. Carbamazepine (CBZ)-succinic acid (SA) was selected as a model cocrystal for this study. A Design of Experiments (DoE) approach, specifically Central Composite Design (CCD) with the aid of Response Surface Methodology (RSM) was used to optimize formulation variables for the synthesis of carbamazepine and succinic acid cocrystals using slurry crystallization. Design was applied for studying the effect of four independent variables (time, molar ratio, temperature, and concentration) on the yield. The experimental outcome indicated that the molar ratio significantly affects the yield of the cocrystal. Further, the optimized formulation was characterized by powder X-ray diffraction. It can be found that within a certain range, all obtained are pure cocrystal.
Cocrystallization is a novel method for designing and developing new multi-component crystalline solids with unique packing characteristics [
In this study, time, molar ratio, temperature, and concentration are critical process parameters (CPPs); the purity and yield of CBZ-SA cocrystal are critical quality attributes (CQAs). The purpose is to illustrate the correlation between purity and yield through experimental design and mathematical models, establish a design space with multiple indicators overlapping, select a better operating space, and finally perform process verification.
CBZ and SA were purchased from Energy Chemical (Shanghai, China). HPLC-grade ethanol was purchased from Shanghai Lingfeng Chemical Reagent Co., Ltd. (Shanghai, China).
CBZ-SA cocrystal was synthesized using a slurry crystallization method as previously described. Typical, Carbamazepine (236 mg) and succinic acid (118 mg) were precisely weighed and the CAB-SA cocrystal was synthesized using a slurry crystallization.
A Central Composite Design (CCD) generated using version 8 Design Expert® software (Stat-Ease Inc., Minneapolis, MN, USA) was selected for the optimization of process variables for the synthesis of CBZ-SA cocrystal using slurry crystallization. The experiments conducted for the CCD are listed in
According to the existing research results and a large number of analysis comparisons, crystallization temperature, crystallization time, material molar ratio and material concentration are selected as influencing factors, and the yield of CBZ-SA cocrystal is used as the evaluation index (response value). It is confirmed that when the crystallization temperature is 20˚C - 60˚C, the crystallization time is 2 - 6 h, the material molar ratio is 1:3 - 3:1, and the material concentration is 0.1 - 0.5, the yield can basically reach the maximum.
The four-factor five-level central comprehensive experimental design method was used to perform quadratic multiple regression equation fitting and optimization analysis. Perform the test according to the factor codes and levels are shown in
X-ray powder diffraction patterns were collected using Ultima IV series X-ray diffraction, Cu-Kα radiation of λ = 0.154 nm and a nickel filter. Samples were placed onto a silicon wafer slide. Generator settings were 40 kV with a current of 40 mA used for the measurement. Data were collected (n = 3) in the range 2θ = 5˚ to 40˚ at a scanning rate of 5˚/min with a scan rate of 0.04˚/time and a slit width of 6.0 mm. The X-ray diffraction data were treated using evaluation curve fitting software. Baseline correction was performed on each diffraction pattern by subtracting a spline function fitted to the curved background and the diffraction pattern of uncoated nano cocrystals was used for reference purposes.
| Level | Time/h | Molar ratio/g・mL−1 | Temperature/˚C | Concentration/mol・L−1 |
|---|---|---|---|---|
| 2 | 10 | 3:1 | 20 | 0.5 |
| 1 | 8 | 2:1 | 30 | 0.4 |
| 0 | 6 | 1:1 | 40 | 0.3 |
| −1 | 4 | 1:2 | 50 | 0.2 |
| −2 | 2 | 1:3 | 60 | 0.1 |
A summary of the input variables used to optimize the manufacture of cocrystal identified using the CCD is summarized in
The test results show that when the conditions of influencing factors are: time 4 h, molar ratio 2:1, temperature 30˚C, and concentration 0.4 mol・L−1, the maximum yield is 84.32%.
| Experiment order | Time | Molar ratio | Temperature | Concentration | Yield/% |
|---|---|---|---|---|---|
| 1 | 1 | 1 | 1 | 1 | 82.20 |
| 2 | −1 | 1 | −1 | 1 | 79.24 |
| 3 | 0 | 0 | 2 | 0 | 61.20 |
| 4 | 2 | 0 | 0 | 0 | 64.50 |
| 5 | 0 | 0 | 0 | 0 | 62.15 |
| 6 | −1 | 1 | −1 | −1 | 68.64 |
| 7 | 1 | 1 | −1 | 1 | 83.05 |
| 8 | 1 | −1 | 1 | −1 | 49.26 |
| 9 | 0 | 0 | 0 | 0 | 66.38 |
| 10 | 1 | 1 | −1 | −1 | 72.46 |
| 11 | −1 | −1 | −1 | −1 | 46.08 |
| 12 | 0 | 0 | 0 | 0 | 62.61 |
| 13 | 0 | 0 | 0 | 0 | 63.56 |
| 14 | 0 | 2 | 0 | 0 | 75.26 |
| 15 | 1 | −1 | 1 | 1 | 64.35 |
| 16 | 0 | 0 | 0 | 0 | 60.26 |
| 17 | 1 | −1 | −1 | 1 | 50.85 |
| 18 | −1 | −1 | 1 | 1 | 59.59 |
| 19 | 0 | 0 | 0 | −2 | 11.30 |
| 20 | 0 | 0 | 0 | 0 | 57.44 |
| 21 | −2 | 0 | 0 | 0 | 47.08 |
| 22 | 0 | −2 | 0 | 0 | 42.37 |
| 23 | 1 | 1 | 1 | −1 | 76.69 |
| 24 | −1 | −1 | 1 | −1 | 49.79 |
| 25 | 0 | 0 | −2 | 0 | 67.78 |
| 26 | −1 | 1 | 1 | −1 | 72.88 |
| 27 | 0 | 0 | 0 | 2 | 72.03 |
| 28 | −1 | −1 | −1 | 1 | 61.18 |
| 29 | −1 | 1 | 1 | 1 | 84.32 |
| 30 | 1 | −1 | −1 | −1 | 41.31 |
Use Design-expert 8 to perform multiple regression fitting on the experimental results in
The results of the analysis of variance are shown in
Analysis of variance shows, Model significance of the equation P = 0.0052 < 0.05, R2 = 0.9724, It shows that the equation has good fit and small experimental error, which can be used to predict and analyze the yield of carbamazepine cocrystal.
The regression equation coefficient significance experiment results show that the first term B has a significant effect on the yield of carbamazepine cocrystal, the interaction term AB is significant, the quadratic terms C2 and D2 are significant, and the other terms are not significant.
| Source | Sum Of Squares | Degree Of Freedom | Mean Square | F-Value | P-Value |
|---|---|---|---|---|---|
| model | 5391.22 | 14 | 385.09 | 4.09 | 0.0052 |
| A | 46.18 | 1 | 46.18 | 0.49 | 0.4945 |
| B | 2878.76 | 1 | 2878.76 | 30.57 | <0.0001 |
| C | 22.25 | 1 | 22.25 | 0.24 | 0.6339 |
| D | 1822.31 | 1 | 1822.31 | 19.35 | 0.0005 |
| AB | 25.48 | 1 | 25.48 | 0.27 | 0.6106 |
| AC | 11.21 | 1 | 11.21 | 0.12 | 0.7349 |
| AD | 2.41 | 1 | 2.41 | 0.026 | 0.8750 |
| BC | 7.38 | 1 | 7.38 | 0.078 | 0.7833 |
| BD | 8.11 | 1 | 8.11 | 0.086 | 0.7732 |
| CD | 1.00 | 1 | 1.00 | 0.011 | 0.9195 |
| A2 | 0.20 | 1 | 0.20 | 2.130E−003 | 0.9638 |
| B2 | 19.44 | 1 | 19.44 | 0.21 | 0.6561 |
| C2 | 140.16 | 1 | 140.16 | 1.49 | 0.2413 |
| D2 | 325.66 | 1 | 325.66 | 3.46 | 0.0827 |
| Residual | 1412.64 | 15 | 94.18 | ||
| Underfitting | 1366.83 | 10 | 136.68 | 14.92 | 0.0040 |
| Pure Error | 45.81 | 5 | 9.16 | ||
| Total Variation | 6803.86 | 29 |
Use Design-expert 8 software to optimize the multiple regression model of carbamazepine cocrystal yield, and predict that under the optimal crystallization conditions: crystallization time is 4 h, material molar ratio is CBZ:SA = 2:1, When the crystallization temperature is 30˚C and the material concentration is 0.4, the maximum yield of CBZ-SA cocrystal is 84.32%. For the four factors of crystallization time, crystallization temperature, material molar ratio and material concentration, when two of them are selected as fixed values, the response surface and contour lines of the other two factors and their interaction on the yield of carbamazepine eutectic are as follows: As shown in Figures 1-6, the shape of the contour lines can reflect the strength of the interaction effect. An ellipse indicates a significant interaction effect, while a circle is the opposite.
The XRD of carbamazepine and succinic acid is shown in
1) In this study, the Design-expert8 software was used to optimize the multiple regression model of CBZ-SA cocrystal yield, and the optimal crystallization conditions were predicted: when the crystallization time was 4 h, material molar ratio was CBA:SA = 2:1, crystallization temperature at 30˚C and a material concentration of 0.4 mol・L−1, the maximum yield of CBZ-SA cocrystal was 84.32%.
2) The multiple regression model equations of the coding independent variables crystallization temperature, crystallization time, material molar ratio and material concentration were obtained: R1 = 61.86 + 1.39A + 10.95B + 0.96C + 8.71D + 1.26AB + 0.84AC − 0.39AD − 0.68BC − 0.71BD − 0.25CD + 0.086A2+ 0.84B2 + 2.26C2 − 3.45D2.
3) The characteristic peaks in the powder diffraction pattern of the CBZ-SA cocrystal had changed significantly, and the peak positions and peak shapes were completely different, at 2θ = 5.68˚, 11.4˚, 15.32˚, 17˚, 17.2˚, 22.56˚, 26.68˚, 29.76˚. The characteristic peaks attributed to CBZ and SA are significantly smaller.
The current research demonstrated that the slurry crystallization technique can be an effective method in the production of cocrystals with appropriate selection of time, molar ratio, temperature, and concentration. CBZ-SA cocrystals were successfully formulated by integrating the cocrystal preparation technologies. In the preparation method, ethanol was selected as a solvent. Central composite design was successfully used to optimize the formulation and process parameters to get the desired cocrystal. The use of DoE and slurry crystallization to manufacture optimized CBZ-SA is an inexpensive, reproducible and precise method of manufacturing CBZ-SA. Quality of design (QbD) here helps to understand the attributes related to preparation of cocrystal.
Authors sincerely acknowledge and express kind gratitude to all the authors of the publications and other contents used in the writing of this review paper entitled “Optimization of Carbamazepine-Succinic Acid Cocrystal Preparation using quality by design approach”.
The authors declare no conflicts of interest regarding the publication of this paper.
Xia, Y.F., Jiang, C.J. and Zhang, J.N. (2021) Optimization of Carbamazepine-Succinic Acid Cocrystal Preparation Using Quality by Design Approach. Open Access Library Journal, 8: e7074. https://doi.org/10.4236/oalib.1107074