# Stability of Paracetamol Amorphized by Co-Melting with Various Cellulose Derivatives
## 1 Introduction  
The most physically and chemically stable polymorphic form of active pharmaceutical ingredient (API) is usually used to produce pharmaceutical products [1; 2]. However, many APIs exhibit better bioavailability if we use a different (less common) polymorphic or amorphous form [3; 4; 5; 6]. Bioavailability corresponds to the percentage of API that will be absorbed into the blood [7; 8; 9; 10]. The most used parameter to assess bioavailability is the area under curve (AUC) of API concentration in plasma as a function of time. The maximum API concentration in plasma (C\({}_{\text{max}}\)) and the time after which this concentration is reached (T\({}_{\text{max}}\)) are also often used as pharmacokinetic parameters. Bioavailability enhancement is associated with an obvious benefit for patients, as the therapeutic effect can thus be obtained with lower doses of API, leading to a reduction in side effects of pharmacotherapy [11; 12]. The benefit also extends to the pharmaceutical industry, as the ability to reduce the effective dose of a drug reduces the cost of manufacturing a pharmaceutical product, where the API is usually the most expensive ingredient. Reducing the dose is also advantageous for the environment. The result is a reduction in the total amount of API and its metabolites excreted by patients. Pollution of municipal waste with API residues and metabolites is now a significant problem. The search for opportunities to reduce these pollutants is therefore very important for the environment. For many APIs, in addition to the crystalline form, an amorphous form is also known [13; 14]. Usually obtaining this form is not difficult. The main problem in this context is keeping the API in amorphous form and stopping crystallization. In pharmaceutical products, shelf life should be planned in this context, usually for 5-6 years. The usefulness of the amorphous form of API in the final pharmaceutical product depends on the possibility of stopping crystallization. The manufacturing of a pharmaceutical product besides one or more APIs requires the addition of excipients [15; 16]. These agents do not induce an effect on the organism, but only allow the creation of the necessary form, physically and microbiologically stable, providing appropriate technological properties and comfortable dosing. To achieve this, in solid formulations, substances of natural origin (e.g., lactose and mannitol, starch) are used, but also modified natural products, especially various starch derivatives (e.g., modified starch, hydroxymethyl starch) and cellulose derivatives (e.g., microcrystalline cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose). The literature provides information on the possibility of API amorphization under the influence of substances used as excipients [17; 18]. Sometimes the reduction in crystallinity was already possible after the formation of the physical mixture. Often, achieving full amorphization requires the co-melting of the components into a solid dispersion. Especially well-known in this application is the use of hydroxypropyl methyl cellulose (hypromellose, HPMC) [16]. Paracetamol (acetaminophen, N-acetyl-p-aminophenol) is a phenacetin derivative [19]. It is one of the most widely used substances with analgesic and antipyretic effects. Three polymorphic forms of paracetamol are known, plus an amorphous form. For the manufacture of pharmaceutical products, the most stable form I is used. This form melts at approximately 170 \({}^{\circ}\)C and exists like monoclinic crystals [20; 21; 22]. Also relatively stable during storage is form II (orthorhombic), which melts at 157 \({}^{\circ}\)C. This form crystallizes into form I during storage. Form III (metastable) melts at approximately 143 \({}^{\circ}\)C and converts to form II during storage or heating [21; 22].