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Initial Solvent Screening of Carbamazepine, Cimetidine, and Phenylbutazone: Part 2 of 2
The authors describe the importance of a rapid and an abbreviated screening strategy in initial solvent screening. This article contains bonus online-exclusive material.
Solubility studies. When the locations of the 19 solvents were assigned within the 3-D Hansen plot of a dispersion-force component (δd), a polar component (δp), and a hydrogen-bonding component (δh) by their corresponding coordinates (δd, δp, and δh) and all the good solvents and bad solvents were represented by yellow and red, respectively, based on the colors of the
diagonal boxes in the form space of a given API, a cluster of yellow domains was formed. The contour of these yellow domains
outlined a 3-D volume of solubility in space that excluded all the bad solvents by a solubility sphere with center coordinates
(δd, API, δp, API, δh, API) and an interaction radius (RS–API) (12). For the solubility sphere of Form III carbamazepine at 25 °C, δd, API = 21.4 MPa1/2 , δp, API = 17.2 MPa1/2 , δh, API = 13.1 MPa1/2 , and RS–API = 17.6 MPa1/2 . For the solubility sphere of Form A cimetidine at 25°C, δd, API = 26.3 MPa1/2 , δp, API = 17 MPa1/2 , δh, API = 23.8 MPa1/2 , and RS–API = 24.8 MPa1/2 . Finally, for the solubility sphere of Form A phenylbutazone at 25°C, δd, API = 15 MPa1/2 , δp, API = 10 MPa1/2 , δh, API = 10 MPa1/2 , and RS–API = 12.7 MPa1/2 , whose center coordinates (δd, API, δp, API, δh, API) were close to the reported values of 17.5, 12.5, and 10.7 MPa1/2 , respectively, measured by dissolution calorimetry (13).
Table II: Solvent systems of cimetidine.
With the solubility sphere of an API at hand, the solubility power of any new solvent other than the 19 solvents used with
known values of δd, δp, and δh can be predicted instantly. If the coordinates of a new solvent (δd, δp, δh) are located inside the solubility sphere of an API, it is a good solvent with respect to that API. Otherwise, it is deemed
a bad solvent. To verify the validity of the solubility sphere, each sphere of an API was tested with n-propanol (δd = 16 MPa1/2 , δp = 6.8 MPa1/2 , δh = 17.4 MPa1/2 ) and cyclohexane (δd = 16.8 MPa1/2 , δp = 0 MPa1/2 , δh = 0.2 MPa1/2 ). Calculations showed n-propanol to be located inside the Form III carbamazepine's solubility sphere (because D
S - API
= 17.4 MPa1/2 for n-propanol < R
S - API
= 17.6 MPa1/2 for Form III cambamazepine), inside the Form A cimetidine's solubility sphere (because D
S - API
= 23.8 MPa1/2 for n-propanol < R
S - API
= 24.8 MPa1/2 for Form A cimetidine), and inside the Form A phenylbutazone's solubility sphere (because D
S - API
= 8.30 MPa1/2 for n-propanol < R
S - API
= 12.65 MPa1/2 for Form A phenylbutazone). These calculations agreed well with the experimental observations that n-propanol was a good solvent at 25 °C for Form III carbamazepine (solubility = 14.18 mg/mL), for Form A cimetidine (solubility
= 13.7 mg/mL) and for Form A phenylbutazone (solubility = 31.46 mg/mL).
Table III: Solvent systems of phenylbutazone.
However, cyclohexane was calculated to be situated outside the Form III carbamazepine's solubility sphere (because D
S - API
= 23.8 MPa1/2 for cyclohexane > R
S - API
= 17.6 MPa1/2 for Form III cambamazepine), outside the Form A cimetidine's solubility sphere (because D
S - API
= 34.7 MPa1/2 for cyclohexane > R
S - API
= 24.8 MPa1/2 for Form A cimetidine), and outside the Form A phenylbutazone's solubility sphere (because D
S - API
= 15.74 MPa1/2 for cyclohexane > R
S - API
= 12.65 MPa1/2 for Form A phenylbutazone) (12). Once again, the experimental results supported the calculations that cyclohexane was a
bad solvent at 25 °C for all three APIs with a solubility of < 1 mg/mL.
Figure 5: Solubility curves of Form III carbamazepine in 13 solvents.
Most of the good solvents of Form III carbamazepine belonged to Class 1 protic or hydrogen-bond donating solvents (i.e., Lewis
acids), Class 2 hydrogen-bonding acceptor solvents (i.e., Lewis bases), and Class 3 polar aprotic solvents, which disrupted
the N-H···O hydrogen bonds and the C-H···O weak interactions of the carboxamide dimer units existing in the solid state of
all forms of carbamazepine (1, 14). The good solvents for Form A cimetidine were mainly Class 1 solvents that interacted readily
with the weakly basic imidazole ring and disrupted the N-H···N hydrogen bonds of the dimer units existing in the solid state
of Form A cimetidine (6, 8, 14). Finally, the good solvents for Form A phenylbutazone were Classes 1 to 3 solvents, Class
4 chlorocarbon solvents, and Class 5 hydrocarbon solvents. This result implied that the intermolecular interactions in the
crystal lattice of phenylbutazone were dominated by van der Waals forces (dipole–dipole interactions and London dispersion
force) (15).
Figure 6: Solubility curves of Form A cimetidine in five solvents.
