# Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes

^{*}

## Abstract

**:**

## 1. Introduction

## 2. Experimental Section

#### 2.1. Materials

#### 2.2. Additive Screening for the Preparation of Form II PCA

#### 2.3. Effect of Additive Amount on the Polymorphic Formation of PCA

#### 2.4. Effect of Seeding on the Polymorphic Formation of PCA

#### 2.5. Liquid-Assisted Grinding

#### 2.6. Effect of the Degree of Supersaturation on the Polymorphic Formation of PCA with the Assistance of FUM and OXA

#### 2.7. Solubility Measurement in the Aqueous Solutions of FUM and OXA

#### 2.8. Cake Washing for the Removal of FUM

#### 2.9. Batch Additive-Assisted Cooling Crystallization of PCA in a Stirred Vessel

#### 2.10. Continuous Additive-Assisted Cooling Crystallization of PCA in a Tubular Crystallizer

#### 2.11. Instrumental Analysis

^{−1}with a resolution of 2 cm

^{−1}for 8 repetitions.

^{®}F5 column (150 mm × 4.6 mm × 4.6 μm particle size × 8.8 nm pore diameter) and an autosampler were installed in the HPLC system. A mobile phase of phosphoric acid buffer solution was pumped at a flow rate of 1 mL/min at 25 °C. The mobile phase was prepared by dissolving 40 mmol of sodium phosphate monobasic monohydrate and 10 mmol of 85% phosphoric acid in 800 mL of water. Water was then added to a total solution volume of 1 L at a pH of 2.6. The UV wavelength was set at λ = 210 nm.

^{1}H and

^{13}C Nuclear Magnetic Resonance Spectroscopy (NMR). NMR (Bruker Ascend 600 MHz, Germany) was used to identify molecular structures and define their relative stoichiometric ratio(s). An amount of 20 mg of each sample was dissolved in 1 mL of deuterated dimethyl sulfoxide (DMSO-d

_{6}).

## 3. Results and Discussion

#### 3.1. Additive Screening for the Preparation of Form II PCA

#### 3.2. Effect of Additive Amount on the Polymorphic Formation of PCA

#### 3.3. Effect of Seeding on the Polymorphic Formation of PCA

#### 3.4. Effect of the Degree of Supersaturation on the Polymorphic Formation of PCA with the Assistance of FUM and OXA

#### 3.5. Solubility Diagrams of the PCA–FUM and PCA-OXA Aqueous Solutions

_{sp}is defined as:

_{sp}, can be estimated with a slope by plotting [PCA] vs. 1/[OXA] according to Equation (3):

_{11}is a first-order complexation constant. K

_{11}can be written as:

_{sp}of the co-crystal is presented as:

_{total}>> K

_{11}K

_{sp}, Equation (9) can be rewritten to become:

_{total}were fitted based on Equation (10), and therefore, the K

_{sp}and K

_{11}of PCA-OXA co-crystals were estimated using the slope and intercept of the fitting equation in Figure 9 to be 4.15 × 10

^{−4}M

^{2}and 153.91 M

^{−1}, respectively, with an R square of 0.83. The large intercept indicates the formation of a solution complex. However, the solubility points at higher concentrations of OXA shifted away from the fitting curve (Figure 8b).

_{total}was increased above 0.5 M, the slope (i.e., Δ[PCA]

_{total}/Δ[OXA]

_{total}) became positive, leading to a concave upward (U-shaped) solubility curve in Figure 8b. Unlike the present study (all experiments were conducted in water), the K

_{sp}of PCA-OXA co-crystals in acetonitrile was decreased with an increase in [OXA]

_{total}, until [OXA]

_{total}had reached the solubility of OXA [66]. The upward solubility curve is associated with the formation of a high-order solution complex. Nehm et al. had proposed various solubility models for multiple complexes existing in the liquid and solid phases [70]. The solubility trend contributed by multiple complexes would be different from that of a single complex. PCA-OXA

_{2}and PCA

_{2}-OXA were the two possible complexes if a second-order solution complex was formed. However, the trend of Form II PCA usually crystallized in a high concentration of OXA implied that the new solution complex associated with Form II PCA formation should appear in a similar environment. Therefore, in our study, a PCA-OXA

_{2}solution complex was considered rather than a PCA

_{2}-OXA complex. A PCA

_{2}-OXA solution complex might appear in the left region of a 1:1 solution complex (if it existed), but it was less related to Form II PCA. If a 1:2 complex (i.e., PCA-OXA

_{2}) exists, a different complexation constant, K

_{12}, would be applied. [PCA]

_{total}is then given as:

_{total}vs. [OXA]

_{total}is a concave upward curve (U-shaped) and the dependence of co-crystal solubility on their concentration will be significant at high [OXA]

_{total}. The existence of a high-order solution complex is suggested in Figure 8b. In addition, the increase in the solubility of PCA was responsible for the long induction time, especially at high concentrations of OXA.

#### 3.6. Removal of FUM Crystals from the Mixture of Form II PCA and FUM by Solvent Rinsing

#### 3.7. Batch Additive-Assisted Cooling Crystallization of PCA in a Stirred Vessel

#### 3.8. Continuous Additive-Assisted Cooling Crystallization of PCA in a Tubular Crystallizer

## 4. Conclusions

## Supplementary Materials

^{1}H NMR spectrum of Form II PCA produced from the PCA-MAL solution by Screening Method 2. Figure S7: Theoretical diffraction pattern of 1:1 PCA-THP co-crystal and PXRD patterns of the PCA crystals produced by Screening Methods 1 and 2 in the presence of THP. Figure S8: FTIR spectra and OM images of the PCA crystals produced by cooling crystallization with different amounts of ADI. Figure S9: FTIR spectra and OM images of the PCA crystals produced by cooling crystallization with different amounts of FUM. Figure S10: FTIR spectra and OM images of the PCA crystals produced by cooling crystallization with different amounts of MLC. Figure S11: FTIR spectra and OM images of the PCA crystals produced by cooling crystallization with different amounts of OXA. Figure S12: FTIR spectra and OM images of the PCA crystals produced by cooling crystallization with different amounts of SUC. Figure S13: OM images of the PCA crystals produced by batch cooling crystallization. Figure S14: OM images of the PCA crystals produced by batch cooling crystallization with FUM. Figure S15: OM images of the PCA crystals produced by batch cooling crystallization with OXA. Figure S16: Temperature profiles determined at nine different positions in the tubular crystallizer with two flow rates of 75 and 150 mL/min.

## Author Contributions

## Funding

## Acknowledgments

## Conflicts of Interest

## References

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**Figure 1.**Phase transitions of nine PCA polymorphs (T

_{m}, melting temperature; T

_{c}, crystallization temperature; and T

_{g}, glass transition temperature).

**Figure 3.**PXRD patterns of the PCA crystals produced by (

**a**) Screening Method 1 and (

**b**) Screening Method 2 with different additives as compared to Form I PCA (purchased) and Form II PCA (prepared by reaction coupling) on the top. The characteristic diffraction peaks of Form I PCA, Form II PCA, ADI, and FUM are labeled by ☐, ✴, △, and +, respectively.

**Figure 4.**OM images of the PCA crystals produced by Screening Method 1 with (

**a**) ADI, (

**b**) FUM, (

**c**) MAL, (

**d**) MLC, (e) OXA, (

**f**) SUC, and (

**g**) THP, and by Screening Method 2 with (

**h**) ADI, (

**i**) CAF, (

**j**) FUM, (

**k**) MAL, (

**l**) MLC, (

**m**) OXA, (

**n**) SUC, and (

**o**) THP. The impurity in (

**k**) is indicated by a circle.

**Figure 5.**PXRD patterns of the PCA crystals harvested by seeding the PCA aqueous solutions with (

**a**) Form I PCA, (

**b**) Form II PCA, (

**c**) ADI, (

**d**) FUM, (

**e**) MLC, (

**f**) OXA, and (

**g**) SUC. The characteristic peaks of Form I PCA and Form II PCA are labeled by ☐ and ✴, respectively.

**Figure 6.**PXRD patterns of the PCA crystals harvested by seeding the PCA–additive aqueous solutions with (

**a**) ADI, (

**b**) FUM, (

**c**) MLC, (

**d**) OXA, and (

**e**) SUC. The characteristic peaks of Form I PCA, Form II PCA, ADI, and FUM are labeled by ☐, ✴, △, and +, respectively.

**Figure 7.**The types of PCA polymorphs with respect to the degree of supersaturation of PCA in aqueous solutions.

**Figure 8.**Solubility diagrams of PCA in the aqueous solutions with various concentrations of (

**a**) FUM and (

**b**) OXA at 10 °C. The solubility values of PCA in water and aqueous solutions of FUM and OXA are labeled by ▼, ●, and ■, respectively, whereas the solubility values of FUM and OXA in water are labeled by ▶ and ◀, respectively. The solid line in (

**b**) is a fitting curve based on Equation (10) where K

_{sp}and K

_{11}could be obtained in Figure 9.

**Figure 10.**(

**a**) Solubility values of Form I PCA (●) and FUM (${\u25a0}$) in NaAc (aq) at different concentrations at 10 °C and (

**b**) the weight fractions of PCA and FUM in the product on a filter cake after rinsing with 1 M NaAc (aq).

**Figure 11.**PXRD patterns of (

**a**) the PCA crystals produced by cooling crystallization in 50 wt% of FUM and rinsed with 15 mL of 1 M NaAc (aq) at 10 °C (

**b**) 2, (

**c**) 3, and (

**d**) 4 times. The characteristic diffraction peaks of Form II PCA and FUM are labeled by ✴ and +, respectively.

**Figure 12.**(

**a**–

**c**) OM images and (

**d**–

**f**) PXRD patterns of the PCA crystals produced by batch cooling crystallization (

**a**,

**d**) without an additive, and at (

**b**,

**e**) 20 wt% and (

**c**,

**f**) 50 wt% of FUM under no agitation in the 0.5 L vessel (scale bar = 200 μm). The characteristic diffraction peaks of Form I PCA, Form II PCA, and FUM are labeled by ☐, ✴, and +, respectively.

Additive | Screening Method 1 | Screening Method 2 |
---|---|---|

ADI | Form II PCA + ADI | Form I PCA + ADI |

CAF | No crystal | PCA-CAF |

CIT | Form I PCA | Form I PCA |

FUM | Form II PCA + FUM | Form II PCA + FUM |

GLU | Form I PCA | Form I PCA |

MAL | Form I PCA | Form II PCA |

MAO | Form I PCA | Form I PCA |

MLC | Form I PCA | Form II PCA |

OXA | Form I PCA | Form II PCA |

SUC | Form II PCA | Form II PCA |

THP | PCA-THP + Form II THP | PCA-THP + Form II THP |

TAR | Form I PCA | Form I PCA |

**Table 2.**Composition of the products harvested by the cooling crystallization of PCA with the assistance of additives at different weight ratios of PCA to additives based on PXRD.

Additive | Weight Ratio of PCA to Additive | Weight Percentage of Additive (wt%) | Composition |
---|---|---|---|

ADI | 1:0.25 | 25 | Form I PCA |

1:0.5 | 50 | Form II PCA + ADI | |

1:0.75 | 75 | Forms I + II PCA + ADI | |

1:1 | 100 | Forms I + II PCA + ADI | |

FUM | 1:0.1 | 10 | Form I PCA |

1:0.2 | 20 | Form II PCA + FUM | |

1:0.3 | 30 | Form II PCA + FUM | |

1:0.5 | 50 | Form II PCA + FUM | |

MLC | 1:0.25 | 25 | Form I PCA |

1:0.5 | 50 | Form I PCA | |

1:0.75 | 75 | Form I PCA | |

1:1 | 100 | Form I PCA | |

OXA | 1:0.3 | 30 | Form I PCA |

1:0.6 | 60 | Form I PCA | |

1:0.9 | 90 | Forms I + II PCA | |

1:1.2 | 120 | Form II PCA | |

SUC | 1:0.25 | 25 | Form I PCA |

1:0.5 | 50 | Form I PCA | |

1:0.75 | 75 | Forms I + II PCA | |

1:1 | 100 | Form II PCA |

**Table 3.**Composition of the PCA products by batch cooling crystallization using the 0.5 L vessel in Expt. 1 to 20.

Expt. | Additive | Weight Percent (%) | Agitation Speed (rpm) | Induction Temperature (°C) | PCA Yield (%) | Composition |
---|---|---|---|---|---|---|

1 | - | - | 300 | 52 ± 2.7 | 81.17 ± 0.83 | Form I PCA |

2 | - | - | 200 | 38.3 ± 1.6 | 80.75 ± 0.74 | Form I PCA |

3 | - | - | 100 | 38.8 ± 1.4 | 77.94 ± 0.89 | Form I PCA |

4 | FUM | 20 | 300 | 40.9 ± 2.9 | 79.47 ± 5.33 | Form I PCA + FUM |

5 | FUM | 20 | 200 | 41.1 ± 1.8 | 82.97 ± 1.84 | Form I PCA + FUM |

6 | FUM | 20 | 100 | 33.2 ± 4.3 | 77.91 ± 3.01 | Form I PCA + FUM |

7 | FUM | 50 | 300 | 43.7 ± 4.5 | 79.06 ± 2.26 | Form I PCA + FUM |

8 | FUM | 50 | 200 | 38.8 ± 6.4 | 80.76 ± 1.71 | Form I PCA + FUM |

9 | FUM | 50 | 100 | 39.2 ± 4.3 | 78.47 ± 3.32 | Form I PCA + FUM |

10 | OXA | 60 | 300 | 34.9 ± 6.2 | 70.94 ± 2.85 | Form I PCA |

11 | OXA | 60 | 200 | 33.5 ± 6.8 | 71.94 ± 2.01 | Form I PCA |

12 | OXA | 60 | 100 | 27.8 ± 9.1 | 70.23 ± 3.73 | Form I PCA |

13 | OXA | 120 | 300 | 23.8 ± 11.3 | 60.71 ± 17.29 | Form I PCA |

14 | OXA | 120 | 200 | 17.8 ± 0.8 | 58.06 ± 5.39 | Form I PCA |

15 | OXA | 120 | 100 | 19.8 ± 3.5 | 57.48 ± 3.11 | Form I PCA |

16 | - | - | - | 33.9 ± 5.3 | 73.74 ± 4.51 | Form I PCA |

17 | FUM | 20 | - | 18.2 ± 5.7 | 66.64 ± 5.46 | Forms I + II PCA + FUM |

18 | FUM | 50 | - | 28.2 ± 2.8 | 72.26 ± 3.72 | Forms I + II PCA + FUM |

19 | OXA | 60 | - | 11.2 ± 1.1 | 21.21 ± 7.62 | Form I PCA |

20 | OXA | 120 | - | 11.2 ± 1.2 | 1.91 ± 1.40 | Form I PCA |

**Table 4.**Composition of the PCA products by continuous cooling crystallization using the tubular crystallizer in Expt. 21 to 28.

Expt. | PCA (g) | FUM (wt%) | Flow Rate (mL/min) | Yield (%) | Product Composition | |
---|---|---|---|---|---|---|

Collected from Outlet | Remaining in the Crystallizer | |||||

21 | 20 | 20 | 75 | 1.4 | Form I PCA | Form I PCA + FUM |

22 | 20 | 20 | 150 | 0.15 | Forms I + II PCA | Form I + II PCA + FUM |

23 | 20 | 30 | ˙75 | 0.35 | Forms I + II PCA + FUM | Form I + II PCA + FUM |

24 | 20 | 30 | 150 | 0.4 | Forms I + II PCA + FUM | Form I + II PCA + FUM |

25 | 20 | 50 | 75 | - | Clogging | Form I PCA + FUM |

26 | 20 | 50 | 150 | 0.15 | Form II PCA + FUM | Form II PCA + FUM |

27 | 15 | 50 | 75 | 4.27 | Form I PCA + FUM | Forms I + II PCA + FUM |

28 | 15 | 50 | 150 | 3.13 | Form II PCA + FUM | Form II PCA + FUM |

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## Share and Cite

**MDPI and ACS Style**

Yeh, K.-L.; Lee, H.-L.; Lee, T.
Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes. *Pharmaceutics* **2022**, *14*, 1099.
https://doi.org/10.3390/pharmaceutics14051099

**AMA Style**

Yeh K-L, Lee H-L, Lee T.
Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes. *Pharmaceutics*. 2022; 14(5):1099.
https://doi.org/10.3390/pharmaceutics14051099

**Chicago/Turabian Style**

Yeh, Kuan-Lin, Hung-Lin Lee, and Tu Lee.
2022. "Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes" *Pharmaceutics* 14, no. 5: 1099.
https://doi.org/10.3390/pharmaceutics14051099