Introduction

The pH of an aqueous solution is a critical factor to be considered for all those medications prepared in aqueous liquid forms. The potential effect of pH on solubility will be a decisive factor for the stability of the medications to be administered. Moreover, the biological tolerability of the formulation can be compromised, as well as the activity of the active principle (AP)¹.

The solubility of acid and basic drugs is pH-dependent, and based on its ionization constant, which creates a balance between the ionized and non-ionized species, and leads to the dilution of the acid and/or the base. Aqueous reactions are generally catalyzed by pH. There have been studies measuring the degradation rates at different pH values, keeping constant the temperature, ionic strength, and concentration of the solvent. The conclusion of these studies was that, if pH is not within a maximum stability range, the non-ionized form of the drug will prevail, leading to the creation of insoluble precipitates².

Each AP has a pH range for its maximum stability, and it can lose activity outside this range, due to physical and chemical transformations. The combination with diluents, excipients, and other medications with a different pH, can trigger undesired effects and compromise the stability of the formulation. It has been confirmed that, for example, folic acid and furosemide will precipitate at a pH below 8 and 7, respectively; omeprazole is degraded at pH values below 7.8; propranolol breaks down if exposed to alkaline pH values, and captopril experiences oxidative degradation in means presenting pH values above 4³.

Therefore, pH determination is important for the preparation of oral liquid formulations (OLFs), because it affects the solubility, activity, absorption, biological tolerability and stability of the AP^4,5.

However, most formulation guidelines with acknowledged prestige about OLFs for pediatric patients, such as: “Formulación Pediátrica Manuela Atienza”, “Standardised formulations for New Zealand”, “Nationwide Children´s Hospital”, “Hospital for Sick Children” and “University of Michigan College of Pharmacy”, do not include any pH values for maximum stability of the preparations described. On the other hand, the Spanish National Formulary (FNE) includes in its procedure No. PN/L/CP7001/00 the determination of pH as quality control for solutions, suspensions and syrups, but exclusively for formulations prepared in lots^{6 7 8 9 10-11}.

Given the lack of compatibility data between OLF components, we hereby state that knowing the pH values for maximum stability of the medications to be administered is a predictive factor that can prevent serious stability problems, and that its determination will ensure the quality and efficacy of the formulations prepared.

The objective of this study is to determine the optimal pH range for the OLFs more frequently prepared at the Hospital Pharmacy Unit (HPU), in order to standardize and incorporate said value into the standard work procedures (SWPs) as a quality control criterion.

Methods

A retrospective study was conducted on the preparation records of all OLFS prepared at the HPU from January, 2015 to December, 2016. Those OLFS prepared with a ≥ 5 frequency were selected, and the pH values evaluated were collected. Mean value and standard deviation were calculated for each preparation, as well as the range, obtained through the difference between the maximum and minimum values recorded. These pH determinations were conducted with a sensION^TMpH31 meter^®.

In order to determine the maximum stability pH of the AP, the following bibliographic sources were reviewed: the product specifications of the molecules by our main provider (www.acofarma.com/es/formulación-magistral/fichas-tecnicas) and the books: Trissel´s “Stability of Compounded Formulations” 2nd edition, and “Handbook of Extemporaneous Preparation” (2010), as well as the product specifications by the Spanish Agency of Medicines and Medical Devices (AEMPS) for branded medications to be administered intravenously as solution, and the United States Pharmacopeia 32th edition and National Formulary 27th edition (USP 32- NF 27)^{12 13 14 15-16}.

The most relevant pediatric formulation guidelines previously mentioned were also consulted^{6 8 9-10}.

Finally, the pH values recorded were compared with the maximum stability values stated in the bibliography, and an acceptance range was determined for each of the OLFs evaluated.

Results

In total, 31 OLFs were reviewed according to the criteria of the first stage of the study: 14 solutions and 17 suspensions (Table 1.1) (Table 1.2) (Table 1.3). For all OLFs prepared during the period of the study, and which met the inclusion criteria, the following data were collected: pH mean value, standard deviation, and pH ranges for the same SWP (Table 2). The latter value ranged between 0.32 and 1.51.

Table 1. Formulation and composition of the OLFs prepared at the HPU 

Table 1. (cont.). Formulation and composition of the OLFs prepared at the HPU 

Table 1. (cont.). Formulation and composition of the OLFs prepared at the HPU 

amp: ampoules; caps: capsules; q.s. for: quantity sufficient for; q.s.: quantity sufficient.

Table 2. pH mean value, standard deviation and range for each compound preparation 

After consulting the different bibliographical sources in order to find the maximum stability pH of the AP, only the value of the 19 (61.3 %) of the APs and/or OLFs evaluated was available.

Regarding the formulation guidelines consulted, a pH value as quality control was determined for 3 (9.7%) of the OLFs selected in the “Formulación Pediátrica Manuela Atienza”; 10 (32.3%), in the “Standardised formulations for New Zealand”, 1 (3.2%) in the “Nationwide Children´s Hospital”, 1 (3.2%) in the “University of Michigan College of Pharmacy”, and none in the “Hospital for Sick Children”.

The data on maximum stability pH for APs and OLFs referenced in the bibliography selected appear inTable 3.

Table 3. Maximum stability pH values for the active principle and pH values of the oral liquid formulations described in the bibliography reviewed 

AP: active principle; OLFs: oral liquid formulations; UNKN: unknown.

Of those 19 OLFs and/or PAs with a known pH range for maximum stability, 15 (78.9%) were within said range, and the remaining 4 (21.1%) presented a ± 0.5.standard deviation.

Based on the data collected in the bibliography consulted, and the variability of the determinations evaluated, it was determined to include pH as regular quality control for SWPs with a ± 0.75 acceptance range.

Discussion

The pH is one of the factors with higher impact on the stability of a formulation in aqueous solution. Knowing the maximum stability pH for an AP of OFLs is essential to guarantee the quality of the preparation; it must remain stable during all the validity and preservation period established¹.

In most of the formulation guidelines reviewed, pH is not included either as a control to be conducted or an acceptance range; a pH range for each monograph is only described in USP 32- NF 27. In the FNE, pH determination (PN/L/CP/001/00) is included as a product control procedure, and it is compulsory for all solutions, suspensions, syrups and gels prepared in lots^11,16.

It is worth highlighting that there is limited bibliography providing data on the pH values for maximum stability of an AP and/or OLF.

Given that there are many medications, such as furosemide, propranolol, omeprazole and captopril, with an already known and well defined pH for maximum stability, and the formulation is not stable unless within it, we consider that this is a value that must be known and evaluated, even for individualized formulations not prepared in lots⁵. The SWP established should include this criterion.

For those OLFs with unknown maximum stability pH range, or insoluble AP, pH determination is still a quality indicator, because it must stay stable and reproducible for the same SWP, as has been demonstrated in the study.

Even though the HPU evaluated and recorded pH routinely for all individual OLFs, there was no acceptance range established for each SWP. This study has been useful in order to include this criterion in the protocol, and its evaluation as quality control.

Knowing the maximum stability pH in the preparation of an OLF, and determining an acceptance range as quality control, are indispensable requirements for an adequate galenic validation, and to guarantee treatment efficacy.