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[9]                                                                                                                                                                                                                                                 AJDHS.COM 

 

 

Available online at ajdhs.com 

Asian Journal of Dental and Health Sciences 
Open Access to Pharmaceutical and Medical Research 

Copyright  © 2022 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 
which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the 

original author and source are credited 
 

 

 

Effect of pH on Pharmaceutical Ingredients / Drugs / Chemicals 

Md Amir, Md Ashfaque Alam, Md Fauwaz Aftab, Md Gulam Nabi, Md Sadre Alam, Dr. Jagdeesh Rathi, Sonpal 
Singh Thakur* 

NRI Institute of Pharmaceutical Sciences, 1, Sajjan Singh Nagar, Opposite Patel Nagar, Raisen Road Bhopal 462022, MP, India 

Article Info: 
_______________________________________ 
Article History: 
Received 03 July 2022      
Reviewed 21 Aug 2022 
Accepted 27 Aug 2022 
Published 15 Sep 2022 

_______________________________________ 
Cite this article as:  

Amir M, Alam MA, Aftab MF, Nabi MG, Alam MS, 

Rathi J, Thakur SS, Effect of pH on 
Pharmaceutical Ingredients / Drugs / 
Chemicals, Asian Journal of Dental and Health 
Sciences. 2022; 2(3):9-11 

DOI: http://dx.doi.org/10.22270/ajdhs.v2i3.17                                     

_______________________________________
*Address for Correspondence:   

Sonpal Singh Thakur, NRI Institute of 
Pharmaceutical Sciences, 1, Sajjan Singh Nagar, 
Opposite Patel Nagar, Raisen Road Bhopal 
462022, MP 

Abstract 
___________________________________________________________________________________________________________________ 
The word excipient is derived from the Latin excipere meaning to except, which is simply explained as 
other than. Pharmaceutical excipients are basically everything other than the active pharmaceutical 
ingredient. Ideally, excipients should be inert, however, recent reports of adverse reactions have 
suggested otherwise. Pharmaceutical excipients are substances other than the active pharmaceutical 
ingredient (API) that have been appropriately evaluated for safety and are intentionally included in a 
drug delivery system. Solubility, which defines the liquid /solid equilibrium, is a key parameter to 
control a crystallization process. As the API is a weak acid (pKa = 3.7), its solubility increases with the 
pH. On the basis of the experimental curve of solubility, a model was defined to fit the evolution of the 
solubility as a function of pH. In the case of this compound, studies revealed a weak influence of the 
temperature in comparison with the pH. So, the solubility of the compound is slightly impacted by the 
temperature. Some experiments were carried out in order to compare the solubility of the API, at the 
same pH and temperature, for different concentrations of impurities found in the process. The results 
revealed a solubility increase in presence of acetic acid and a high solubility decrease in presence of 
sodium chloride. By carrying out experiments on common ions salts, the anion chloride Cl− has been 
identified as the cause of the solubility decrease. 

Keywords: Solubility, API, Impurity, Ph 

 

Introduction 

In pharmaceutical industries, the control of active 
pharmaceutical ingredient (API) crystal properties is 
necessary because these properties will define the 
pharmaceutical form of the medicine elaborated with the 
crystals. As the generation step of these crystals, the 
crystallization process has to be controlled 1,2. For this, one of 
the initial data needed is the solubility of the product in the 
mother solution. The API crystals are obtained by an acid-base 
precipitation. The pH is then the main parameter of the 
precipitation because it has a direct impact on the API 
solubility. The knowledge of the evolution of the solubility as a 
function of pH is then needed in order to control the 
precipitation. Moreover, in the considered process, at the end 
of precipitation, the remaining solution in which crystals are 
suspended contains impurities such as sodium chloride and 
acetic acid. These impurities have an influence on the 
solubility of the API. As filtration and washing steps are 
necessary to purify crystals, the knowledge of the solubility is 
also paramount to determine the loss of product by 
dissolution during these steps 3, 4. 

Definition of partition coefficient (pKa) 

When a weak acid dissociates in solution according the 
scheme below (1), we can express the acid 1onization 
constant (Ka) using equation (2). The negative logarithmic 
form of the acid 1onization constant (3) is more commonly 
used. Rearrangement of equation (3) affords the Henderson-

Hasselbalch equation (4). In a similar manner we can employ 
these equations for the conjugate acid forms of basic functional 
groups (5). 

HA + H2O ⇌ A + H3O
+ 

(1) 

Ka= A H3O+ HA            (2) 

pKa = log10Ka            (3) 

pH=pKa+log A AH            (4) 

BH
+ 

+ H2O ⇌ B + H3O
+    

(5) 

Material and Methods 

Chemicals 

Sodium hydroxide 

Molecular weight- 39.997g/mol 

Chemical formula- NaOH 

Sodium chloride 

Molecular weight- 58.44g/mol 

Chemical formula – NaCl 

Hydrochloric acid 

Molecular weight- 36.458 g/mol 

Chemical formula –HCl 

                       Open Access                                                                                                                                                                                                        Research Article                                                                           

http://jddtonline.info/
http://dx.doi.org/10.22270/ajdhs.v2i3.17
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641858/#FD2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641858/#FD3
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641858/#FD4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641858/#FD4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641858/#FD5
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641858/#FD6


Amir et al                                                                                                                                        Asian Journal of Dental and Health Sciences. 2022; 2(3):9-11 

[10]                                                                                                                                                                                                                                                 AJDHS.COM 

Ammonium chloride 

Molecular weight- 53.491g/mol 

Chemical formula -NH4Cl 

Apparatus 

 PH meter 

 Measuring Cylinder-5ml 

 Volumetric flask- 100ml 

 Pipette-5ml 

 Beaker- 100ml 

 Glass rod 

 

Experimental 

Sodium Hydroxide 

Table 1: API solubility as a function of Sodium Hydroxide 
concentration, at 20°C 

NaOH 

concentration 
(mol/L) 

Solubility (mol/L) pH 

0.00 0.0478 3.60 

0.78 0.39997 3.57 

0.95 0.395973 3.53 

0.99 0.3799 3.50 

1.21 0.4839 3.48 

1.84 0.73597 3.44 

2.65 1.05992 3.42 

3.55 1.41989 3.40 

 

Sodium Chloride 

Table 2: API solubility as a function of sodium chloride 
concentration, at 20°C 

NaCl concentration 
(mol/L) 

Solubility (mol/L) pH 

0.00 0.0477 2.60 

0.68 0.0359 2.57 

0.86 0.0326 2.53 

0.98 0.0321 2.50 

1.37 0.0273 2.48 

1.95 0.0212 2.44 

2.74 0.0153 2.42 

3.42 0.0133 2.40 

 

 

 

 

 

Hydrochloric Acid 

Table 3: API solubility as a function of Hydrochloric Acid 
concentration, at 20°C    

HCL 

concentration (mol/L) 

Solubility (mol/L) pH 

0.00 0.2943 5.60 

0.78 0.2843 5.57 

0.89 0.3244 5.53 

0.99 0.36093 5.50 

1.38 0.5031 5.48 

1.96 0.71451 5.44 

2.75 1.00259 5.42 

3.43 1.2578 5.40 

 

Ammonium Chloride 

Table 4: API solubility as a function of Ammonium Chloride 
concentration, at 20°C 

NH4CL 

concentration (mol/L) 

Solubility (mol/L) pH 

0.00 0.0497 4.60 

0.79 0.0.225 4.57 

0.89 0.4760 4.53 

0.99 0.5295 4.50 

1.38 0.73817 4.48 

1.96 1.08442 4.44 

2.75 1.47100 4.42 

3.43 1.8347 4.40 

 

Results 

NaOH is strong base, so this will produce 0.1 mol/L of OH ion 
solution. This will produce a pH of 13. To summarize, NaCl 
decrease the solubility and reduce the activity of hydrogen ion, 
the net effect is a small reduction in PH (by about 0.01). The 
PH of the hydrochloric acid is 2 according to the given data 
which indicates that it is acidic in nature. The PH value of the 
solution will decrease (basically less than7) as the solution 
will become slightly acidic (PH value 4.5 to 6). 

Conclusion  

This study focused on the main parameters influencing the 
solubility of an API. As it is a weak acid, it has been proven that 
the pH is the most important parameter and a model has been 
built to follow its evolution. The temperature revealed to be a 
less significant parameter but permitted to determine the 
enthalpy of dissolution of the API. Finally, impacts of the 
process impurities have been characterized. Considering the 
effects of hydration of ions, the presence of a kosmotropic 
anion explained the API solubility decrease observed. 

 

 

 



Amir et al                                                                                                                                        Asian Journal of Dental and Health Sciences. 2022; 2(3):9-11 

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