Paracetamol also referred to as acetaminophen is an antipyretic and analgesic drug that is widely applicable. It is present both in liquid form as suspensions and solutions as well as in solid dosage forms such as tablets, suppositories and capsules. These drugs belong to the class of drugs referred to as “aniline analgesics” and in fact it is the only one in this class that is still in use presently. Paracetamol is the active metabolite of phenacetin. However, it differs with phenacetin and its combination in that it is not regarded as being carcinogenic in therapeutic doses.
The words paracetamol and acetaminophen are derived from the chemical name para-acetylaminophenol which has the following structure; In the beginning, paracetamol was detected in the urine of patients who were under phenacetin. In 1889, a demonstration took place showing that paracetamol is acetamilide’s urinary metabolite. Five years later, 1893, paracetamol was discovered as an odourless bitter crystalline compound which was white in colour. However, the aforementioned discoveries did not attract much attention hence were ignored at that point in time.
More than fifty years later, in 1948, there was a resurgence of interest that was experienced as far as paracetamol is concerned. This was done by Axelrod and Brodie who found out that paracetamol was a key metabolite of both paracetamol and acetamilide. Being a derivative of p-aminophenol, it corresponds to phenacetin which is the active principle metabolite. At that time, it was a common assumption that the body’s rapid consumption into paracetamol was the one responsible for the therapeutic effects of the two drugs.
Later on, it was established that phenacetin had a pharmacological action of its own which was independent of paracetamol for it to work. Nevertheless, due to high conversion of phenacetin into paracetamol in the liver, there was need to use large dosage of phenacetin so as to attain any direct pain releasing effect. Paracetamol has a chemical formula C8H9NO2 and the following structure. O OH NH In crystalline form, paracetamol molecules are bonded by OH……. O and NH……..
O hydrogen bonds to form chains. These chains are further joined into 2-D networks which further give 3-D layers that are bonded together by van der Waal forces. Paracetamol is therapeutically used for fever reduction (antipyretic) and as a pain killer (analgesic). It is also applied as an ingredient in a number of cold and flu treatments. Paracetamol can be combined with other drugs like codeine and be used as a stronger pain killer to manage very severe pain for example advanced cancer conditions.
In adults, the recommended dose is 2 x 500mg tablets where a maximum of eight tablets are administered in a twenty four hour period. For this drug, overdose is considered to have occurred if twenty four to thirty tablets are taken at a go. For children, a half to one of 500mg tablet can be taken up to six times per day depending on the age of the child. Paracetamol has been reported to exist in three polymorphic forms. However, it is possible to get single crystal structures for only two of them. These are polymorph 1 which is mono clinic and polymorph II which is orthorhombic.
At room temperature/ambient conditions, polymorph I is thermodynamically stable with a melting point of 168-1700C while the second polymorph is metastable with a melting point of 168-1700C. The three crystalline polymorphs are shown below; Polymorph I Polymorph II Polymorph III It is not possible to tablet polymorph I (monoclinic) without using excipients. For polymorph II (orthorhombic), tabletting can easily be done since the structure is more compressible, this phenomenon makes form II to be highly applicable as compared to form I.
Studies of x-ray diffraction have proved that polymorph I and II have the same bulk compressibility even though the anisotropy of lattice strain of the two polymorphs is different. Whereas polymorph I and II have been found to be thermodynamically and metastable respectively, polymorph III has been reported to be unstable and as such there are no crystals that have been isolated for the determination of the physical and chemical properties of this polymorph. Haisa et al conducted single crystal x-ray diffraction at -1500C (123K) to confirm the structure and identity of polymorphs I and II.
Compaction simulation was also used to determine the compaction properties of the two crystalline polymorphs. Unit cell parameters for both form I and II at ambient conditions (room temperature) have been reported. This has been compared with data that is available from already published works (literature). Further, the crystal morphologies of both polymorph I and II were simulated and the obtained models compared to morphologies of crystals that were experimentally grown. From this research study, it was concluded that compressibility of paracetamol decreases with an increase in polymorph I.
Further, it was pointed out that plastic deformation of crystals that occurs under compression is as a result of the typical molecular arrangements characteristic of polymorph II. This structure is made up of parallel planes that have high molecular density. It is also characterised by inter planes bonds that are weak which when subjected to compression they exhibit the behaviour of sliding planes hence causing plastic deformation. The main aim of this study was to give an in depth understanding of the intermolecular forces between paracetamol molecules.
This was done through the investigation of thermal expansion behaviour of the crystals using x-ray powder diffraction technique. The study mainly focused on dimensional changes in the lattice structure as a result of changes in temperature. Studies on thermal expansion behaviour of polymorph I (monoclinic) and polymorph II (orthorhombic) was done by using thermal expansion of copper as the research mode. The whole study was conducted at temperatures between 100K and 450K with the sole aim of refining phase transition temperatures. Objective of the study
Since most of pharmaceutical products are in solid form, for example tablets and capsules, there should be a specification on how the formulation design influences optimal solid dosage forms. The main objective of pharmaceutical development is designing a manufacturing process that delivers a final product that is of high quality. It is worthy to note that testing of pharmaceutical products’ quality is not only done on the final product but is taken care of from design, during the manufacturing process and finally analysis of the finished product.
Phase transformation of pharmaceutical products can unexpectedly be induced by moisture and other related physical stabilities. It is therefore important to ascertain the solid state properties of API and the excipients so as to ensure consistent dosage forms. Therefore, this study looks at the different physical and chemical properties of the polymorphic forms of paracetamol so as to ascertain the exact dosage quantities to be used.