The impact of ionic excipients on stabilization of enalapril tablets by the formation of alkaline salt “in situ”

Abstract

The formation of salts is one of the possibilities of stabilizing medicinal substances. Salts can be prepared during the manufacture of the dosage form, saving time, reducing cost and environmental impact. Several studies have documented significant enalapril maleate (EM) instability. EM decomposes into diketopiperazine (DKP) and diacid (DA) impurities at elevated temperature and humidity. Notably, toxic DKP is preferentially formed at pH 2 – 3, and DA formation dominates at pH values above 5. This instability raises concerns about the therapeutic efficacy and safety of the drug. The proposed stabilization strategy involves the “in situ” conversion of EM into a stable sodium salt. This is achieved by incorporating suitable ionic excipients, specifically alkali metal salts and an ethanol-based hydrolysis inhibitor, into the granulation solution. This method effectively inhibits the deethylation to DA and provides uniform tablets with minimal DKP content to ensure long-term five-year stability. In general, these tablets show a lower content of degradation products compared to the stability results reported so far in various generics, and the amount of impurities meets the ICH Q3B (R2) requirements.

Highlights

The preparation of salts “in situ” can shorten the production of the drugs.

Ionic alkaline excipients convert EM into a stable sodium salt “in situ”.

Ethanol inhibits deethylation during neutralization.

The process guarantees the 5 years long-term stability of tablets.

This technology is environmentally friendly.

Introduction

The formation of salts from pre-existing substances is an effective method for improving the physicochemical properties of APIs, such as stability, solubility, bioavailability, and processability [1]. Typically, a solvent-mediated process is used to produce salts, where the use of large amounts of solvent has a detrimental impact on the environment [2]. However, there is a possibility to include salt formation as part of the drug product manufacturing process, where a larger amount of an environmentally friendly liquid is used, for example during granulation for suitable APIs. Good solubility of the given API and neutralizing agent in the used volume of the granulation liquid are prerequisites [3]. This step eliminates the neutralization step in the synthesis of the API and this chemical reaction takes place “in situ” only during the production of the dosage form [4]. No technological step is added.

For neutralization, it is possible to use substances that have been commonly used in pharmaceutical technology for many years, such as alkali metal ions [3]. It is possible to advantageously produce salts of acidic substances. APIs in this form can be neutralized for example with sodium or potassium carbonates and bicarbonates. These excipients have been used for decades in tablet manufacturing as disintegrants because they react with gastric acid to produce carbon dioxide, which then disrupts the tablet structure and accelerates its disintegration [5]. Although used for a different purpose, they are safe and therefore also permitted for the manufacture of medicinal products. This strategy can also be used to innovate existing APIs, provided that the new form is not considered a new drug. Moreover, alkali salts of API revert to the original API in the stomach, and thus do not represent a new chemical identity [4,6]. A model substance is enalapril, whose sodium salt is considered equivalent to the original enalapril maleate (EM). EM reacting with sodium carbonate to form the sodium salt exhibits higher stability [7,8].

EM, an angiotensin-converting enzyme (ACE) inhibitor, is a widely used antihypertensive medication. However, its stability presents a significant challenge because EM reacts readily under conditions of elevated temperature and moisture. EM undergoes decomposition into two primary products under these conditions: the diketopiperazine (DKP) and the diacid (DA) impurity. DKP formation occurs through internal nucleophilic cyclization, while DA arises from the hydrolytic cleavage of the ethoxy carbonyl group [9,10]. The relative abundance of these degradation products is pH dependent. At a pH below 3, DKP predominates, whereas DA becomes the main product at a pH exceeding 5 [11]. The mechanism of chemistry is shown in Fig. 1.

DA is also an active metabolite arising from the first passage through the liver (first pass effect) and acts as an inhibitor of angiotensin converting enzyme [12]. DKP is a toxic product. Ethyl ester in the form of maleate enables better absorption from the gastrointestinal tract [13].
The form of commonly used excipients is decisive for stabilization. Their particle size distribution affects formulation stability. Substances with a larger surface area tend to absorb water, leading to hydrolysis of EM [14,15]. Therefore, the EM alone has higher stability during stress tests (increased temperature, humidity) than after mixing with other excipients [16]. The mechanical shock during compression causes further instability of the resulting dosage form [8], and it can be mitigated by coating the substance with a thin film of a polymer from a series of cellulose derivatives [17]. An effective way of protection is also the formation of β-CD complexes with EM preventing the formation of DKP in the solid form DKP I [18].

Oxidation is another undesirable reaction. Taking place mainly on the surface of the dosage form, it manifests itself in color changes. To solve this problem, a dosage form containing excipients with antioxidative properties, e.g. the antioxidant ascorbic acid, or its sodium salt is recommended, while a synergistic effect is achieved by combining it with hydrogenated cottonseed oil [19]. Alternatively, technological modifications such as the creation of hot melt granules [20,21], or hydrophobized microparticles [22] also led to stabilization. In the case of tablets, the dosage form can be effectively protected from external influences such as oxygen, for example by a double aluminum foil or glass tubes [23]. Therefore, hydrolysis due to moisture in the tablet remains the main source of EM instability [24,25].

The pH of the microenvironment in pharmaceutics plays a decisive role in managing EM instability caused by hydrolysis. Therefore, pH-adjusting by ionic excipients is essential to maintain the optimal pH and prevent this type of degradation. By setting the pH of the buffering environment in the range of 5.5 – 7.0, the proportion of DKP formed will decrease [26]. The combined addition of alkaline ionic substances and carbohydrates, both serving as excipients, can enhance stability of EM tablets. This includes, for example, lactose and mannitol in combination with borates or carbonates of sodium, magnesium, and calcium [27]. A small addition of organic acids, regulating the microenvironment in the tablet, also leads to increased stability [7,28].

During pH treatment by neutralization, EM salts, primarily sodium salts, are frequently formed. This modification is generally accepted by regulatory authorities, making the addition of alkali metal salts a common practice in EM-containing tablet formulations [4]. However, alkaline salts of weak acids revert to their original form in the acidic stomach environment [6]. Despite improvement in stability by EM alkaline salt formation, it is important to note that the underlying problem may be the inherent tendency of EM to hydrolyze to DA by cleavage of ethanol from the ester bond during neutralization. When reacting, the pH changes continuously and even a slight decomposition in the different pH of solution with dissolved EM can lead to exceeding permissible limits [29].

The aim of this research was to formulate a stable dosage form containing 5, 10 and 20 mg of EM by neutralization with suitable excipients. Stabilization of the tablets was performed by an “in situ” neutralization technique with a suitable ionic alkaline excipient in ethanol solution inhibiting hydrolysis, used for wet granulation. This solution represents a direct and cost-effective approach compared to current stabilization methods. It was confirmed that the resulting tablets meet all mandatory pharmacopoeial criteria.