# Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs

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## Abstract

**:**

## 1. Introduction

## 2. Materials and Methods

#### 2.1. Materials

#### 2.2. Preparation of PVP Solutions

#### 2.3. Thermogravimetric Analysis of PVP

#### 2.4. Equilibrium Solubility of the Drugs in PVP Solutions

#### 2.5. Quantitative Analysis

^{2}> 0.98) (Appendix A), and samples were analyzed using Waters Empower Software (version 3.0 build 3471, Milford, MA, USA).

#### 2.6. Viscosity of Solutions of PVP

^{−1}were investigated using 5 points per decade. The pressure was adjusted to 2 bars, and the measurements were carried out at 37 °C. The experiments were performed in triplicates with a sample volume of about 1–2 mL. Microsoft Excel (Redmond, WA, USA) was used for data analysis. Based on the behavior of the PVP solutions as non-Newtonian fluids, a shear rate at the constant viscosity plateau at 631 s

^{−1}was chosen to determine the solution viscosity (Appendix B and Appendix C).

#### 2.7. Nucleation and Crystal Growth of Drugs in a Supersaturated Solution

^{2}= 0.999). Standard curves were prepared with six replicates by adding aliquots of 15 µL DMSO stock solution of the drug to the dissolution medium. The initial concentration of the drug was determined by using the highest concentration of the drug for which no instantaneous precipitation occurred. Precipitation was detected by a deviation from the linearity of the standard curve, a sharp shift in the baseline in the UV spectrum or through visual inspection of the solution. To induce supersaturation, 100 µL of a DMSO stock solution of the drug was transferred into glass vials containing 10 mL solutions of PVP K15, K30, K60 or K120. The concentrations of albendazole, ketoconazole and tadalafil in the DMSO stock solutions were 1, 8 and 6 mg/mL, respectively.

#### 2.8. Data Analysis

_{ind}) and the slope of the time–concentration profile were determined using TA Instruments Trios software (New Castle, DE, USA). The induction time of the time–concentration profile in minutes was estimated using the onset time function via the tangent. The slope of the time–concentration profile in (µg/mL)/min was estimated using the slope function.

#### 2.9. Statistical Analysis

_{ind}and slope from the time–concentration profiles were used as the response values, whereas PVP concentration and the viscosity of the PVP solutions were used as the input predictors. It should be noted that the viscosity of the PVP solutions is used instead of the molecular weights of PVP, and therefore, the impact of the viscosity of solutions of PVP is the same as that of the molecular weight. The three levels for the concentration factor were 0.1, 0.5 and 1% (w/v), and the four levels for the viscosity factor were the viscosities of the solutions of PVP K15, K30, K60 and K120. The multiple linear regression coefficient plot displayed regression coefficients with 95% confidence interval. A factor was considered to have a significant influence if the standard deviation did not cross zero.

_{ind}and slope of time–concentration profile during supersaturation of the drugs are given as the mean ± standard deviation (SD). To assess statistically significant differences between groups, the obtained results were subjected to a one-way analysis of variance (ANOVA), followed by Tukey’s pairwise comparison. Microsoft Excel (Redmond, WA, USA) was used for this analysis. The criteria for determining statistical significance in all tests were set at p < 0.05.

## 3. Results and Discussion

#### 3.1. Influence of PVP Concentration and Molecular Weight on the Solubility of the Drugs

#### 3.2. Influence of PVP Concentration and Molecular Weight on Solution Viscosity

#### 3.3. Supersaturation Studies

_{ind}) of the time–concentration profiles of the respective drugs was used as a surrogate for the onset of nucleation and the slope of the time–concentration profiles was used as a surrogate for the precipitation rate of the respective drugs (Appendix D).

#### 3.3.1. Influence of PVP Concentration, Solution Viscosity and Molecular Weight on the t_{ind} of the Drugs

_{ind}generally increased with increasing concentrations of PVP K15, K30, K60 and K120 from 0.1 to 0.5% (w/v) and again from 0.5 to 1% (w/v) compared to the t

_{ind}in the absence of PVP (Figure 4).

_{ind}of albendazole and tadalafil when increasing the PVP concentration from 0.1 to 0.5% (w/v) and again from 0.5 to 1% (w/v), respectively (Figure 4A,B).

_{ind}of ketoconazole when increasing the PVP concentrations from 0.1 to 0.5% (w/v) and again from 0.5 to 1% (w/v) (Figure 4C). In contrast, in a solution of PVP K30, no statistically significant increase (p > 0.05) in the t

_{ind}of ketoconazole was found when increasing the PVP concentration from 0.1 to 0.5% (w/v). However, ANOVA showed a statistically significant increase (p < 0.05) in the t

_{ind}of ketoconazole when increasing the PVP concentration from 0.5 to 1% (w/v). Additionally, in solutions of PVP K60 and K120, ANOVA showed no statistically significant differences (p > 0.05) of the t

_{ind}of ketoconazole when increasing the PVP concentration from 0.1 to 0.5% (w/v) and again from 0.5 to 1% (w/v).

_{ind}of albendazole and tadalafil when decreasing the degree of supersaturation of the drugs [7]. In contrast, a previous study investigated the influence of PVP K30 on the onset of the nucleation of bicalutamide from a supersaturated solution and found no significant effect of PVP. It was speculated that this could be explained by the critical nucleus size being slightly larger than the size of the repeating monomer unit of PVP [20].

_{ind}in the presence of the same concentrations of PVP K15, K30, K60 and K120 at concentrations of 0.1, 0.5 and 1% (w/v) as can be seen in Figure 5 for 0.1% (w/v) PVP and Figure A5, Figure A6 and Figure A7 for 0.5 and 1% (w/v) PVP. This can be explained by the number of potential binding sites of PVP staying the same, irrespective of the PVP molecular weight, i.e., the same amount of repeating monomer units when using the same concentration [21]. This means that the molecular weight of PVP has no significant influence on the onset of nucleation and, consequently, also that the viscosity of the PVP solution has no influence on the onset of the nucleation of the drug from a supersaturated solution. These results are in line with a previous study that showed no correlation between the solution viscosity and the t

_{ind}of supersaturated nifedipine in solutions of either 0.05% (w/v) PVP K17, K25 or K30 or 0.05% HPMC E3, E5, E6, E15 or E50 [22].

#### 3.3.2. Influence of PVP Concentration, Solution Viscosity and Molecular Weight on the Precipitation Rate of the Drugs

#### 3.3.3. Multivariate Evaluation of the Influence of Concentration and Solution Viscosity on t_{ind} and Precipitation Rate of the Drugs

_{ind}and precipitation rate of the drugs from supersaturated solutions.

_{ind}and slope of the time–concentration profile, while the viscosity of the PVP solution has no significant influence on either t

_{ind}or slope of time–concentration profile (Figure 7).

## 4. Conclusions

_{ind}and a decrease in the slope of the time–concentration profiles of albendazole, tadalafil and ketoconazole. However, the t

_{ind}for ketoconazole in the presence of solutions of PVP K60 and K120 did not increase when increasing the PVP concentration from 0.1 to 0.5% (w/v) and again from 0.5 to 1% (w/v). These findings can be explained by drug–polymer interactions such as hydrogen bonds or dipole–dipole forces leading to an increase in drug solubility and thereby a reduction in the degree of supersaturation that in turn increases the t

_{ind}and decreases t

_{ind}precipitation rate of the drugs. Moreover, the t

_{ind}and slope of the time–concentration profile were not statistically significantly different (p > 0.05) between PVP K15, K30, K60 and K120 at the same concentrations. Finally, supersaturation studies in isoviscous solutions of PVP confirmed that solution viscosity has a negligible influence on the t

_{ind}and the slope of the time–concentration profile of the drugs. In conclusion, this study showed that an increasing concentration of PVP in solution increases the onset time of nucleation and decreases the precipitation rate of the drugs, which can be explained by molecular interactions between the drug and polymer. In contrast, no significant influence of the viscosity of the dissolution media was seen for the onset of nucleation and the precipitation rate of the drugs, meaning that the molecular mobility of the drug in solution has no influence on the precipitation inhibition of the drug.

## Author Contributions

## Funding

## Institutional Review Board Statement

## Informed Consent Statement

## Data Availability Statement

## Acknowledgments

## Conflicts of Interest

## Appendix A

**Figure A1.**Standard curves for determination of the equilibrium solubility of the albendazole R

^{2}= 0.997 (

**A**), tadalafil R

^{2}= 0.999 (

**B**) and ketoconazole R

^{2}= 0.989 (

**C**) (n = 3) (mean ± SD).

## Appendix B

**Figure A2.**Viscograms of the solutions of PVP K15 at the concentrations of 0.1, 0.5 and 1% (w/v) (n = 3) (mean ± SD).

## Appendix C

## Appendix D

**Figure A4.**Time–concentration profiles of supersaturated solutions of albendazole (

**A**), tadalafil (

**B**) and ketoconazole (

**C**) in phosphate buffer (n = 8) (mean ± SD).

**Figure A5.**Time–concentration profiles of supersaturated solutions of albendazole in solutions of PVP K15 (

**A**), K30 (

**B**), K60 (

**C**) and K120 (

**D**) at the concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

**Figure A6.**Time–concentration profiles of supersaturated solutions of tadalafil in solutions of PVP K15 (

**A**), K30 (

**B**), K60 (

**C**) and K120 (

**D**) at the concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

**Figure A7.**Time–concentration profiles of supersaturated solutions of ketoconazole in solutions of PVP K15 (

**A**), K30 (

**B**), K60 (

**C**) and K120 (

**D**) at the concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

## References

- Price, D.J.; Ditzinger, F.; Koehl, N.J.; Jankovic, S.; Tsakiridou, G.; Nair, A.; Holm, R.; Kuentz, M.; Dressman, J.B.; Saal, C. Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations—A PEARRL review. J. Pharm. Pharmacol.
**2019**, 71, 483–509. [Google Scholar] [CrossRef] [PubMed] - Savjani, K.T.; Gajjar, A.K.; Savjani, J.K. Drug Solubility: Importance and Enhancement Techniques. ISRN Pharm.
**2012**, 2012, 195727. [Google Scholar] [CrossRef] [PubMed] - Blaabjerg, L.I.; Grohganz, H.; Lindenberg, E.; Löbmann, K.; Müllertz, A.; Rades, T. The influence of polymers on the supersaturation potential of poor and good glass formers. Pharmaceutics
**2018**, 10, 164. [Google Scholar] [CrossRef] [PubMed] - Warren, D.B.; Benameur, H.; Porter, C.J.H.; Pouton, C.W. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility. J. Drug Target.
**2010**, 18, 704–731. [Google Scholar] [CrossRef] - Schöpe, H.J.; Bryant, G.; Van Megen, W. Two-step crystallization kinetics in colloidal hard-sphere systems. Phys. Rev. Lett.
**2006**, 96, 175701. [Google Scholar] [CrossRef] - Meng, F.; Gala, U.; Chauhan, H. Classification of solid dispersions: Correlation to (i) stability and solubility (II) preparation and characterization techniques. Drug Dev. Ind. Pharm.
**2015**, 41, 1401–1415. [Google Scholar] [CrossRef] [PubMed] - Palmelund, H.; Madsen, C.M.; Plum, J.; Müllertz, A.; Rades, T. Studying the Propensity of Compounds to Supersaturate: A Practical and Broadly Applicable Approach. J. Pharm. Sci.
**2016**, 105, 3021–3029. [Google Scholar] [CrossRef] - Garekani, H.A.; Ford, J.L.; Rubinstein, M.H.; Rajabi-Siahboomi, A.R. Highly compressible paracetamol: I: Crystallization and characterization. Int. J. Pharm.
**2000**, 208, 87–99. [Google Scholar] [CrossRef] - Pakuro, N.I.; Arest-Yakubovich, A.A.; Nakhmanovich, B.I.; Chibirova, F.K. Thermo- and pH-Sensitivity of Poly(N-Vinylpyrrolidone) in Water Media. In Polymer Phase Behavior; Nova Science Publisher: Hauppauge, NY, USA, 2011; pp. 296–301. [Google Scholar]
- Raghavan, S.L.; Trividic, A.; Davis, A.F.; Hadgraft, J. Crystallization of hydrocortisone acetate: Influence of polymers. Int. J. Pharm.
**2001**, 212, 213–221. [Google Scholar] [CrossRef] - Fornells, E.; Fuguet, E.; Mañé, M.; Ruiz, R.; Box, K.; Bosch, E.; Ràfols, C. Effect of vinylpyrrolidone polymers on the solubility and supersaturation of drugs; a study using the Cheqsol method. Eur. J. Pharm. Sci.
**2018**, 117, 227–235. [Google Scholar] [CrossRef] - Hong, S.; Nowak, S.A.; Wah, C.L. Impact of Physicochemical Properties of Cellulosic Polymers on Supersaturation Maintenance in Aqueous Drug Solutions. AAPS PharmSciTech.
**2018**, 19, 1860–1868. [Google Scholar] [CrossRef] [PubMed] - Tros de Ilarduya, M.C.; Martín, C.; Goñi, M.M.; Martínez-Ohárriz, M.C. Solubilization and interaction of sulindac with polyvinylpyrrolidone K30 in the solid state and in aqueous solution. Drug Dev. Ind. Pharm.
**1998**, 24, 295–300. [Google Scholar] [CrossRef] [PubMed] - Patel, D.D.; Anderson, B.D. Maintenance of supersaturation II: Indomethacin crystal growth kinetics versus degree of supersaturation. J. Pharm. Sci.
**2013**, 102, 1544–1553. [Google Scholar] [CrossRef] [PubMed] - Knopp, M.M.; Nguyen, J.H.; Becker, C.; Francke, N.M.; Jørgensen, E.B.; Holm, P.; Holm, R.; Mu, H.; Rades, T.; Langguth, P. Influence of polymer molecular weight on in vitro dissolution behavior and in vivo performance of celecoxib:PVP amorphous solid dispersions. Eur. J. Pharm. Biopharm.
**2016**, 101, 145–151. [Google Scholar] [CrossRef] - Plum, J.; Bavnhøj, C.G.; Eliasen, J.N.; Rades, T.; Müllertz, A. Comparison of induction methods for supersaturation: Amorphous dissolution versus solvent shift. Eur. J. Pharm Biopharm.
**2020**, 152, 35–43. [Google Scholar] [CrossRef] [PubMed] - Joshi, P.; Mallepogu, P.; Kaur, H.; Singh, R.; Sodhi, I.; Samal, S.K.; Jena, K.C.; Sangamwar, A.T. Explicating the molecular level drug-polymer interactions at the interface of supersaturated solution of the model drug: Albendazole. Eur. J. Pharm. Sci.
**2021**, 167, 106014. [Google Scholar] [CrossRef] - Kumara, P.; Mohanb, C.; Uma Shankara, M.K.S.; Gulatia, M. Physiochemical characterization and release rate studies of solid dispersions of Ketoconazole with Pluronic F127 and PVP K-30. Iran J. Pharm. Res.
**2011**, 10, 685–694. [Google Scholar] - Mistry, P.; Mohapatra, S.; Gopinath, T.; Vogt, F.G.; Suryanarayanan, R. Role of the Strength of Drug-Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions. Mol. Pharm.
**2015**, 12, 3339–3350. [Google Scholar] [CrossRef] - Lindfors, L.; Forssén, S.; Westergren, J.; Olsson, U. Nucleation and crystal growth in supersaturated solutions of a model drug. J. Colloid Interface Sci.
**2008**, 325, 404–413. [Google Scholar] [CrossRef] - European Chemicals Agency (ECHA). Guidance for Monomers and Polymers; European Chemicals Agency: Helsinki, Finland, 2012.
- Chavan, R.B.; Thipparaboina, R.; Kumar, D.; Shastri, N.R. Evaluation of the inhibitory potential of HPMC, PVP and HPC polymers on nucleation and crystal growth. RSC Adv.
**2016**, 6, 77569–77576. [Google Scholar] [CrossRef] - Patel, D.D.; Anderson, B.D. Effect of precipitation inhibitors on indomethacin supersaturation maintenance: Mechanisms and modeling. Mol. Pharm.
**2014**, 11, 1489–1499. [Google Scholar] [CrossRef] [PubMed] - Xie, S.; Poornachary, S.K.; Chow, P.S.; Tan, R.B.H. Direct precipitation of micron-size salbutamol sulfate: New insights into the action of surfactants and polymeric additives. Cryst. Growth Des.
**2010**, 10, 3363–3371. [Google Scholar] [CrossRef] - Sekikawa, H.; Nakano, M.; Arita, T. Inhibitory Effect of Polyvinylpyrrolidone on the Crystallization of Drugs. Chem. Pharm. Bull.
**1978**, 26, 118–126. [Google Scholar] [CrossRef] - Dai, W.G.; Dong, L.C.; Li, S.; Deng, Z. Combination of Pluronic/Vitamin E TPGS as a potential inhibitor of drug precipitation. Int. J. Pharm.
**2008**, 355, 31–37. [Google Scholar] [CrossRef] [PubMed]

**Figure 2.**Equilibrium solubility of albendazole (

**A**), tadalafil (

**B**) and ketoconazole (

**C**) in absence and presence of solutions of 0.1, 0.5 and 1% (w/v) PVP K15, K30, K60 and K120 (n = 3) (mean ± SD). Asterisk (*) indicating statistically significant differences (p < 0.05).

**Figure 3.**Viscosities of the solutions of PVP K15, K30, K60 and K120 at concentrations of 0.1, 0.5 and 1% (w/v) at a shear rate of 631 s

^{−1}(n = 3) (mean ± SD).

**Figure 4.**Induction time (t

_{ind}) of the time–concentration profiles of albendazole (

**A**), tadalafil (

**B**) and (

**C**) ketoconazole in absence and presence of aqueous solutions of PVP K15, K30, K60 and K120 at concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

**Figure 5.**Time–concentration profiles of albendazole (

**A**), tadalafil (

**B**) and ketoconazole (

**C**) in aqueous solutions PVP K15, K30, K60 and K120 at a concentration of 0.1% (w/v) (n = 8) (mean ± SD).

**Figure 6.**Precipitation rates of the time–concentration profiles of albendazole (

**A**), tadalafil (

**B**) and ketoconazole (

**C**) in absence and presence of solutions of PVP K15, K30, K60 and K120 at concentrations of 0.1, 0.5 and 1% (w/v) (n = 8) (mean ± SD).

**Figure 7.**Coefficient plot generated from MODDE11 pro showing the influence of solution viscosity and PVP concentration on the t

_{ind}and precipitation rate of albendazole, tadalafil and ketoconazole.

**Figure 8.**Precipitation rates of the time–concentration profiles of albendazole (

**A**), tadalafil (

**B**) and ketoconazole (

**C**) in ~1 mPa.s isoviscous solutions of PVP K15, K30, K60 and K120 (n = 8) mean ± SD.

K15 | K30 | K60 | K120 | |
---|---|---|---|---|

Concentration (% (w/v)) | 3.13 | 2.81 | 0.33 | 0.25 |

Viscosity (mPa.s) mean ± SD | 0.98 ± 0.03 | 1.05 ± 0.12 | 1.05 ± 0.12 | 1.04 ± 0.04 |

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## Share and Cite

**MDPI and ACS Style**

Odeh, A.B.; El-Sayed, B.; Knopp, M.M.; Rades, T.; Blaabjerg, L.I. Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs. *Pharmaceutics* **2023**, *15*, 1601.
https://doi.org/10.3390/pharmaceutics15061601

**AMA Style**

Odeh AB, El-Sayed B, Knopp MM, Rades T, Blaabjerg LI. Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs. *Pharmaceutics*. 2023; 15(6):1601.
https://doi.org/10.3390/pharmaceutics15061601

**Chicago/Turabian Style**

Odeh, Afnan Bany, Boushra El-Sayed, Matthias Manne Knopp, Thomas Rades, and Lasse Ingerslev Blaabjerg. 2023. "Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs" *Pharmaceutics* 15, no. 6: 1601.
https://doi.org/10.3390/pharmaceutics15061601