Analysis of the Effect of the Tablet Matrix on the Polymorphism of Ibuprofen, Naproxen, and Naproxen Sodium in Commercially Available Pharmaceutical Formulations

Abstract

Pharmaceutical formulations, in addition to the medicinal substance(s), contain added excipients that make it possible to create a pharmaceutical product that exhibits required properties in terms of mechanical, physical, chemical, and microbiological stability. Additionally, these substances can act as release modifiers or improve bioavailability parameters. Literature data indicate that excipients, especially polymeric ones, can also affect the polymorphism of the active substance, resulting in drug bioavailability enhancement or reduction. This influence can be evaluated using thermal and spectroscopic methods. In the study, differential scanning calorimetry (DSC), vibrational spectroscopic studies (Fourier transform infrared spectroscopy, FTIR), Raman spectroscopy, and X-ray diffraction (XRD) assay of ibuprofen, naproxen, and naproxen sodium standards and pharmaceutical preparations containing these medicinal substances in their compositions were carried out. DSC results indicated that a sharp melting peak was observed on the DSC curves of the standards, confirming their crystalline form. DSC results obtained for pharmaceutical formulations also indicated that the enthalpy of melting is sometimes lower than calculated from the percentage of active ingredients in the formulations. In addition, the melting peak is often broadened and shifted toward lower temperatures, suggesting the influence of excipients on the polymorphism of drug substances. The FTIR and Raman spectra of pharmaceutical formulations contained all characteristics of the active substances. XRD analysis was also performed. Therefore, possible chemical interactions between the components of the preparations have been excluded. At the same time, FTIR and Raman spectroscopy results as well as XRD assay showed a reduction in the height of signals corresponding to the crystalline API form, confirming the possibility of reducing API crystallinity in pharmaceutical formulations.

Introduction

Pharmaceutical products, apart from the active pharmaceutical ingredient (API) or APIs, also contain excipients [1,2,3,4]. The appropriate selection of excipients may be related to the effect on API polymorphism and, at the same time, on bioavailability.

As excipients in solid formulations, substances acting as diluents, binders, disintegrants, lubricants, and sometimes colorants are mainly used [4,5,6]. Cellulose derivatives (hypromellose, methylcellulose, ethylcellulose, microcrystalline cellulose), sugars (lactose, sucrose), and phosphates (dibasic calcium phosphate) are mainly used as diluents. Their role is to give the product the right volume and mass, especially when the amount of API is small. Starch derivatives (pregelanized starch), synthetic polymers (polyvinylpyrrolidone, PVP), or microcrystalline cellulose are used as binders. The role of these ingredients is to physically integrate the components of the solid formulation after product administration. The role of disintegrants is to efficiently dissolve the formulation after administration, ensuring that the API is released within a sufficiently short time after administration. Starch derivatives (starch carboxymethyl ether or sodium starch carboxymethyl ether) and cross-linked polymers (crospovidone, croscarmellose sodium) are used as binding agents. During the development of solid formulations, lubricants are also added, most commonly stearic acid or magnesium stearate. The purpose of these ingredients is to ensure that after the tableting process, the finished tablet is easily removed from the tablet matrix without damaging the tablet press.

A significant limitation in achieving the desired therapeutic effect is bioavailability, which refers to the percentage of the dose that penetrates the bloodstream after product administration [7,8]. For many APIs, low bioavailability is a serious limitation in pharmacotherapy and necessitates the administration of higher doses to achieve a therapeutic effect. Numerous reports in the literature indicate that substances used as excipients may influence API polymorphism [9,10,11,12]. Research into this effect is of great importance, as a change in polymorphic form, partial or complete amorphization, usually leads to improved bioavailability. An API in amorphous form usually exhibits better bioavailability compared to the most stable crystalline form used in pharmaceutical production.

Most often, the effect of excipients on APIs involves obtaining an amorphous form after co-melting the API with a polymeric excipient [13,14,15]. One of the processes used to obtain melted mixtures of APIs and excipients is hot-melt extrusion (HME). The advantage of this solution is that there is no need to add solvents during the process [12,16]. Obtaining an amorphous form using traditional methods requires the use of solvents, which often have a negative impact on the environment.

In many cases, partial reduction of API crystallinity is also possible without melting, after homogenization of the components in the solid phase [15,17,18,19]. Such interactions are particularly interesting because the preparation of a powder mixture for tableting usually involves the creation of a physical mixture of solid ingredients by mixing them for many hours. Sometimes, due to the properties of the powder mixture, it is necessary to carry out an additional granulation process [20,21]. In this process, small powder particles are bonded together into agglomerates. This procedure requires the addition of a binder, which is usually an aqueous polymer solution. The material must then be dried, which requires exposing the granules to high temperatures. Water and elevated temperatures can further initiate transformations leading to polymorphic changes or reduced crystallinity. The stage of pharmaceutical product manufacturing in which polymorphic transformations may also occur is tableting [9]. During this process, the product is subjected to high pressure, which increases the likelihood of polymorphic transformations. Research into the impact of individual excipients on API polymorphism is very important because it helps to understand the nature of these interactions and to better select excipients for APIs at the product design stage. However, due to the specificity of the tablet matrix and the possible influence of the manufacturing process, it is necessary to monitor API polymorphism in the final pharmaceutical product.

The literature provides evidence that the reduction in ibuprofen crystallinity may occur after homogenization with cross-linked polyvinylpyrrolidone (PVP-CL) [16]. A fully amorphous form can be obtained by co-grinding ibuprofen with kaolin [22] or in the HME process after co-melting ibuprofen with hydroxypropylmethylcellulose (HPMC) E5 or Eudragit® E PO [23,24].

The reduction in the crystallinity of naproxen can be achieved by preparing a physical mixture with HPMC, and after melting this mixture, naproxen can be completely amorphized [19]. The reduction in crystallinity of naproxen and naproxen sodium can be achieved by spray drying a mixture of APIs with HPMC [25]. Total amorphization of naproxen is also possible after co-melting with polyvinylpyrrolidone (PVP) [26].

The most-used methods in API and pharmaceutical product testing are gas chromatography (GC), liquid chromatography (LC), and mass spectrometry (MS) [27]. These GC, LC, and MS methods are designed for molecular separation, but they do not allow for the analysis of polymorphic forms. Methods commonly used to study polymorphic and amorphous forms include differential scanning calorimetry (DSC), X-ray diffraction (XRD), and spectroscopy methods in infrared range, most commonly Fourier transform infrared (FTIR), near infrared (NIR) and Raman spectroscopy [21,28,29]. DSC curves enable the assessment of polymorphic forms based on the melting point of the crystalline form, as this value is characteristic and varies depending on the polymorphic form of the substance. In quantitative analysis, the characteristic value in DSC measurements is the heat of melting of the crystalline form. In FTIR, Raman spectroscopy studies how the spectra of individual polymorphic and amorphous forms differ slightly in the position of one or more bands. Similarly, in XRD pattern, a reduction in the height of peaks indicating crystalline form was observed. Sometimes these differences only concern changes in the proportions of the signals.

Download the full article as PDF here Analysis of the Effect of the Tablet Matrix on the Polymorphism of Ibuprofen, Naproxen, and Naproxen Sodium in Commercially Available Pharmaceutical Formulations

or read it here

Leyk, E.; Środa, M.; Maślanka, G.; Nowaczyk, P.; Orzołek, A.; Grodzka, H.; Kurek, A.; Knut, O.; Michalak, J.; Płachciak, J.; et al. Analysis of the Effect of the Tablet Matrix on the Polymorphism of Ibuprofen, Naproxen, and Naproxen Sodium in Commercially Available Pharmaceutical Formulations. Methods Protoc. 2025, 8, 99. https://doi.org/10.3390/mps8050099