Crystallization Process of Paracetamol Behaviour - Term Paper Example

Crystallisation Process of Paracetamol Behaviour 1. Introduction a. Uses of Paracetamol A widely used medicine and known as an analgesic and antipyretic, paracetamol is a mild painkiller and decreases the temperature of patients with fever. There are at present more than ninety familiar products containing paracetamol, which are available over the counter from drug stores (Ellis et. al. 2002, p.3). Paracetamol is acetaminophen and are practical substitute to aspirin, as analgesics and antipyretics. Different from aspirin, their anti-inflammatory activity is inadequate but they lack many of the side effects of aspirin and so were frequently used. Paracetamol is comparatively harmless and safe when taken moderately. However, large amount of paracetamol can cause serious liver damage, which can result in hepatic failure (Koay and Walmsley 1996, p.350). Paracetamol taken in large amount is extremely hepatotoxic because of the production of a minor metabolite or ‘Acetimidoquinone’ (Varcoe 2001 p.59). For adults, the recommended therapeutic dosage of paracetamol is 0.5-1g every 4-6 hours and must not exceed 4 grams daily. Paracetamol is absorbed somewhat quickly from the gastrointestinal tract and forwarded to the liver where it is metabolised. It is then delivered to body’s tissue through blood circulation. While paracetamol is being metabolized in the liver, several metabolites are created. One of them is ‘Acetyl-benzo-quinoneimine’, which is an exceedingly reactive and toxic metabolite. However, a protein from the liver called ‘glutathione’, which protects the liver from cell damage (Courtenay and Butler 1999, p.58), usually detoxifies acetyl-benzo-quinoneimine. b. Polymorphic Structures of Some Compound “A substance capable of existing in more than one crystalline form is said to exhibit polymorphism” (Amiji and Sandman 2002, p.36). The character of the crystallising solvents, as well as the process parameters of crystallization may affect the form isolated at any given time. A conventional illustration of polymorphism originated from nature, which emphasizes the physical and chemical dissimilarities that can be present among polymorphs, is the one existing between hexagonal carbon graphite and cubic diamond. Typical polymorphic substances include sulphur, aspirin, and water, which are enantiotropy, consisting of six to seven dissimilar crystalline forms as ice. In addition, fatty acids, glycerides, fats, almost all crystalline long-chain organics are polymorphic and monotropic. A good example of triglyceride used in pharmacy is the suppository based cocoa butter. Cocoa butter, which must be sufficiently firm at room temperature at 25 degrees centigrade to allow insertion, dissolves at roughly 35 degrees centigrade. This is known as the ‘beta form’, the melting point of the most stable polymorph (Amiji and Sandman 2002, p.36). Polymorphism is essential to pharmaceuticals because each polymorph of a compound contains a distinct crystalline structure and properties such as melting point, solubility, stability, density, hardness, and optical and electrical properties as well as vapour pressure. For instance, if a suspension has two polymorphs, the higher-energy will have a tendency to go into solution and the lower-energy form may experience crystal growth and agglomeration like ‘cortisone’ acetate. Drug substance strength may also be different for amorphous and crystalline forms. For instance, the amorphous form of sodium and potassium penicillin is unsteady to dry heat while their crystalline form was constant to high temperature for a number of hours. The presence of polymorphs can be detected by numerous methods such as infrared spectra, differential thermal analysis, microscopy, and more clearly by x-ray powder diffraction. Amorphous substances demonstrate unremarkable x-ray patterns and these forms are usually more rapidly soluble since there are no crystal lattice forces necessary to be overcome by the solvent (Avis et. al. 1996, p.153). c. Polymorphic Structures of Paracetamol In most cases, polymorphism describes numerous potential shapes for a single property. The polymorphism of any element or compound is its capacity to crystallize as more than one distinctive crystal species. This ability is exceeding widespread in relation with drug substances, which are predominantly minute unadulterated molecules with molecular weights below 600g mol-1 (Hilfiker 2006, p.1) Paracetamol exhibits polymorphism and it is known to exist in two polymorphic forms, monoclinic and orthorhombic. The initial form is more thermodynamically constant at room temperature and is the commercially used form. On the other hand, this form is not appropriate for direct compression into tablets and has to be blended with binding agents prior to tableting, a process that is both expensive and time-consuming. Somewhat the opposite, the second form can effortlessly go through plastic deformation upon compaction and it many believed that that this form possess a clear processing advantages over the first form. The orthorhombic form is metastable with respect to the monoclinic form. Monoclinic paracetamol is easily created by crystallisation from aqueous solution and many other solvents but manufacturing of the orthorhombic form is more complex than monoclinic and only achievable on a laboratory scale (Florence and Attwood 2006, p.15). To address the poor compression of paracetamol, the preparation of a new orthorhombic form is essential. Due to its eminent inferior ‘compressional’ properties, commonly obtainable paracetamol materials for direct compression are compounds of paracetamol with gelatine, polyvinylpyrrolidone, starch, or starch derivatives. Because a chemically uncontaminated paracetamol that could be used for direct compression would add up to a better compendial article, a different polymorph was created. The latest form was re-crystallized from dioxane, and their crystals were found to consist of sliding planes that led to good compressibility (Brittain 1999, p.355). 2. Crystallisation of Paracetamol During the early 1990s, “crystallizations were considered more of an art than a science” (Gadamasetti and Braish 2007, p.296). Throughout those years time process chemist normally designs a process that can deliver active pharmaceutical ingredient or API with a definite particle size. Moreover, formulation chemist would use it to design a tablet or capsule appropriate for medical trials or the market. Conversely, a number of events have altered that tradition because significant advances in analytical devices that permit detections of these contaminations at parts per million levels motivated concerns over the safety of small quantities of probable genotoxic impurities in APIs. Innovative and intelligent formulation that are more appropriate for specific markets and can improve the life cycle of drugs have required more specific and fitting particle-size APIs (Gadamasetti and Braish 2007, p.296). To cope with the demands, process chemist turned to crystal engineering science, which came out as a resilient innovative discipline that help in recognizing the forcefulness of the process and the physical properties they require to work out a most advantageous formulations. In conjunction with science, the systems to counter these challenges have also transformed. Molecular modelling has moved from the hands of specialist to emerge a broadly used imaging tool of how molecules pack into the crystal lattice and the influence of that packing on the physical properties of APIs. Moreover, PAT or Process analytical technology also become sophisticated as it now allow observation of crystals growing in real time and help us understand the effect of seeding and mixing on the morphology of particles. Innovative and efficient tools are emerging that would constantly change the art of designing and growing crystals (Gadamasetti and Braish 2007, p.296). The mainstream of the crystallization literature deals with inorganic crystals and the organic chemistry generally involve small organic molecules such as glutamic acid, phenytoin, or paracetamol. The actuality in the pharmaceutical industry is normally more problematic since molecular weights above 1000 g/mole are widespread, and multifaceted molecular structures consequential to the nucleation and growth kinetics in addition to the probability of polymorph formation. In designing an API crystallisation process, there are three sides to bear in mind. The process should reach a convincing yield and purity, the polymorph or solvate has to be the expected one, and the process must be harmless, effortless, and repeatable. To guarantee these qualities, dependable powder properties, such as particle size distribution or PSD, shape, flowability, tablettability, build density, and strength, are essential, all of which are reliant on a dynamic crystallization process (Gadamasetti and Braish 2007, p.297). 2.1 Aspects that led to different structures The occurrence of a certain compound in excess of one crystal structure is regarded as polymorphism thus the compound is believed to be polymorphic and each stable phase of the compound is accepted as a polymorph. Normally, every polymorph is thermodynamically stable in a particular set of temperature and pressure. In a polymorphic compound, the structure of each polymorph may be entirely dissimilar and no structural relation may exist among the various polymorphs (Feng p.258). Various structures can signify both dissimilar chemical bonding and dissimilar schedules of atoms and molecules, and perhaps even different states of aggregation. Chemical compounds are described as being both chemically and physically different from their atomic components. This characteristic is attributed to the actuality that the system in which chemical bonding changes the electron density distribution is reliant on both the electrons and the nuclei concerned. Therefore, all compounds are an explicit and distinctive arrangement of atoms that is also exclusive in nature. The explicit arrangement of atoms must be unique because the atomic and molecular forces are related to the specific arrangement. In reality, it is possible that the “crystal structures for all compounds are distinct” (Irene 2005, p.26). Presence of impurities can radically influence the nucleation, morphology, and chemical properties of crystals. According to Thompson (2003, p.128), the presence of impurities can have sizeable consequence on the kinetics of crystal nucleation, growth morphology, and dissolution. This is because the control of nucleation may result from alteration in the equilibrium solubility or the solution structure, or by physical or chemical adsorption of the impurity on homogenous nuclei. Impurities may be additives that are mixed for a particular objective. For instance, habit alteration or to manipulate crystal dimension, or may be impurities that came from the mixture or degradation of the required product. Structurally interconnected compounds are widespread impurities in pharmaceutical components. These compounds become integrated with shifting efficiencies, and can consequently affect the nucleation and succeeding crystal growth rate of the solute. 2.2 Best Way to make Paracetamol - Crystallisation by Cooling a solution The choice of crystallization method has a significant impact on which form is produced, and for that reason, it undoubtedly sensible to carry out crystallization using a range of methods when searching for polymorphs. A few of the distinguished systems are crystallization by cooling a solution, evaporation, precipitation, vapour diffusion, suspension equilibrium, crystallization from the melt, heat induced transformations, and sublimation (Hilfiker 2006, p.289). Pharmaceuticals are typically obtained by crystallization and in nearly all circumstances; their particle size hardly ever grows greater than one millimetre. Normally, due to their low solubility, the crystals are considerably undersized (Majumdar 2007, p.691). In order for crystallisation to happen, a solution must be ‘supersaturated’ so that solvent contains more dissolved solids thus creating a solid phase of aqueous solution in an industrial setting all industrial crystallizers employ one or more techniques for generating supersaturation like cooling and evaporation. Precipitation is frequently used to crystallizing systems and typically refers to supersaturation being produced through addition of a third component that stimulate a chemical reaction to produce solute with lesser solubility. A frequent attribute of such systems is the quick creation of the solid phase. This type of crystallisation modes normally creates supersaturation at much higher levels than by simple cooling or evaporation. Precipitation means fast crystallisation that generally occurs because of chemical reaction or rapid modification in solubility by adding a third component (Jones 2002, p.61). The form of the equilibrium line, or solubility curve, is essential in deciding the method of crystallisation to be utilized to facilitate crystallisation of a certain substance. Thus, if the curve is sharp for instance, when the substance shows strong temperature reliance of solubility comparable to salts and organic substances, then a cooling crystallization might be suitable. However, if the metastable zone is broad similar to a sucrose solution, adding a seed crystal might be required. This can be advantageous predominantly when a homogeneously sized product is obligatory. On the other hand, when the equilibrium line is reasonably even, then an evaporative process might be required. If the result from either process is depleted, then almost certainly a second solvent can be added to lessen the effectiveness of the first and reduce the residual solution concentration or ‘drowning-out’. If the solute takes place as a consequence of chemical reaction or addition of a common ion, and is insoluble, the precipitation or ‘fast crystallization’ occurs (Jones 2002, p.68). Supersaturation may be created in a number of ways. It can by cooling saturated solution, evaporation of solvent from as saturated solution, addition of a miscible non-solvent to a saturated solution, use of the common ion effect for ionic salts, salting, and reaction to form the solute in situ (Collins et. al. 1997, p.130). Supersaturation can viewed as the concentration of solute in excess of solubility. Supersaturation is commonly articulated in terms of concentration ∆c= C-C* where C = concentration of solution, C* = saturation concentration and ∆c is the ‘concentration driving force’. The solubility C* of paracetamol and its dependence on temperature T (K) is given by C*(T) =2.955x10-4 exp (2.179x10-2 T). In view of the fact that the solution temperature is a function of time, the progression of the solubility is a function of time as well. When the temperature is ramped down, the time-dependence of the temperature is given by the dimensionally consistent equation T (t) = T0 – r; where r is the cooling rate and T0 is the initial temperature. The concentration of the solute in solution, C, in mass of solute/mass of solvent can be defined as : Where Nb is the number of bins, ρ is the density for paracetamol that is ρ = 1.293x103 kg/m3, Msolvent the mass of solvent in kg, minitial the mass of solute introduced in the system in kg, mc, crystallized the mass of solute crystallized in kg and ∆Ni is the total number of crystals of characteristic size Li in the crystallizer. The typical size is defined as the corresponding diameter of a sphere having very similar volume as the crystal (Barthe 2008, p.77). 2.3 Heating and Cooling of chosen way of crystallisation “Control of supersaturation is critical to controlling product quality in batch crystallizers such as particle size distribution, shape and purity” (Korovessi and Linninger 2005, p.179). For crystallization to occur there must be a driving force, which is typically characterized as supersaturation. It can be produce using a range of methods including cooling, evaporation, addition of a separating agent, or reaction. In the cooling method, the solution temperature is cooled lower than the saturation temperature of the solution. However, even if supersaturation provided by slow cooling is an effortless method, the reality that it is a non-isothermal method indicates that any growth temperature-dependent property of the crystal will not be consistent throughout. “If the temperature is lowered stepwise, the growth rate will not be uniform, and rate-dependent properties of the crystal will not be uniform” (Lieth 1977, p.56). The suggested method for controlling supersaturation is to control the cooling curve or create an optimal cooling curve. The main objective of the cooling curve is to cause supersaturation to let some nuclei to form and afterwards restrain cooling so that the original nuclei grow. The cooling curve remains close to the solubility curve during operation and holds the driving force constant. “Optimal cooling can produce larger crystals than natural cooling or linear cooling” (Korovessi and Linninger 2005, p.180). Similarly, controlling evaporation and adding anti-solvents works better. The heat supplied to the crystallizer can be regulated to control the rate of evaporation. Practically the same as cooling, evaporation is restrained so that few nuclei are formed and permitted to grow. Evaporative crystallization is a semi-batch operation as the solvent is being eliminated during operation. The aim of adding anti-solvents is to control the supersaturation, thus anti-solvents are gradually added and not at once. A number of anti-solvents are added to induce nucleation, and then the rest is gradually added to manage both growth and nucleation (Korovessi and Linninger 2005, p.180). 2.4 How paracetamol affect the body, and through the body (in the human cell) Twelve grams or twenty-four tablets of paracetamol is potential fatal in most patients, whereas 7.5 grams may be lethal in high-risk individuals. Paracetamol is metabolized by live conjugation and when this pathway is saturated a toxic metabolite is formed, usually inactivated by glutathione. When glutathione stores run out, this metabolite binds to cell proteins causing cell death (Davey 2002, p.127). With increasing paracetamol concentrations cell glutathione content are progressively depleted and toxicity is greater. In a study according to David and Evans (1993, p.318), showed that lymphocytes from person with glutathione synthetase deficiency were particularly vulnerable to paracetamol metabolites generated by an in vitro microsonal system. 2.5 Paracetamol Absorption Paracetamol is quickly absorbed from the gastrointestinal tract into the blood over a period of 30 minutes to 2 hours for a therapeutic dose. A small amount is removed unaffected in urine but the rest is metabolised in the liver. Similar to other drugs, paracetamol must be manufactured more water soluble for substantial eradication in urine. This is achieved in the liver by artificial conjugation of paracetamol with sulphate, glucuronate, glycine, and phosphate. These water-soluble combinations of paracetamol are non-toxic. Approximately 90% of a swallowed paracetamol dose is removed safely through urine in this manner. The rest of the paracetamol or about 5 to 10% is oxidised in the liver to a highly reactive and toxic free radical called N-acetyl-p-benzoquinone imine or NAPQI. The radical is answerable for the toxic effects of paracetamol. At normal doses of paracetamol, the liver is able to control this potentially harmful NAPQI by reaction with a substance called glutathione, which is produced in the liver. The result of the reaction between NAPQI and glutathione is non-toxic and is removed securely through the urine. If liver could only manufacture glutathione continuously, then paracetamol would not be damaging regardless of the quantity taken. However, regrettably, the case is the other way around because if the suggested dosage is exceeded, the production of NAPQI rise but the capability of the liver to manufacture the inactivating glutathione cannot cope with it and NAPQI build up in the liver cells, upsetting cellular functions and ultimately trigger liver cell death or necrosis. In the absence of immediate treatment, liver cell necrosis becomes widespread, resulting to liver malfunction where liver transplantation is the only treatment choice (Higgins 2000, p.183). 2.6 Controlling the particle size of the crystals Particle size affects the filtration, isolation, and drying kinetics of the active pharmaceutical ingredients or API, and PSD or particle size distribution is one of the most significant quality features that formulation scientist need. Particle size affects the manufacturability of the drug products in terms of flow characteristics, interactions with excipients, and bioavailability (Gadamasetti and Braish 2007, p.297). When a nucleus is formed, it is the smallest sized crystalline unit that can be present in a particular set of conditions. Nonetheless, instantly following the creation of nuclei, they start to grow bigger through the addition of solute molecules to the crystal lattice. This segment of the crystallization process is known as crystal growth. Crystal growth and nucleation controls the final size distribution and shape of the crystals formed. They are also responsible to the purity and the type of imperfection present. Crystals shape can be cubical, tetragonal, orthorhombic, hexagonal, monoclinic, triclinic, and trigonal (Myerson 1999, p.98). Factors that control the size and shape of crystals are of great significance. There are a number of studies of crystals in the past that involved attempts to be familiar with the shape of minerals and of inorganic salts grown from solution corresponding to the inner structures of the crystals and the thermodynamics of crystal growth. Crystals are dense with atoms, molecules, or ions in an endlessly repeating structure. In addition, planes or faces can typify these structures, which can grow. The crystal planes that are present on a developed crystal, together with the relative areas of these faces, establish the general form of the crystal. This general form is commonly recognized as the crystal habit, crystal shape or crystal morphology. These expressions refer to the outer shape of the crystal and the planes in existence, exclusive of the inner structure. The habit of a crystal signifies the shape of the crystal as a whole, devoid of the faces present. It is possible for crystals of the same substance to contain the same arrangement of crystal forms and possess very dissimilar habits. The disparities of crystal habit and crystallographic form are the consequence of the actuality that crystals are the outcome of a growth process that occurs by various dissimilar methods in different environments and at numerous rates (Myerson 1999, p.98). Control of particle size is directly related to flow properties, segregation, and demixing. The connection between particles size and particle surface area is an inverse one as diminution in particle size is consequential to the increase in the surface area. In most pharmaceutical suspensions, the particle diameter is between 1 and 50µm. A current suspension should contain a particle size less than 35µm to be intangible to the touch or else roughness occur. The most competent method of producing particles of most advantageous size is by dry milling prior to inclusion into the dispersion medium. Among several methods of producing small uniform drug particles is micro pulverisation, fluid energy grinding spray drying, and controlled precipitation. Micropulverizers, using rapid abrasion or impact mills are proficient enough to reduce particle size to a satisfactory range for most oral or topical suspensions. Fluid energy grinding is rather efficient in yielding particles below 10 µm in size. Particles that are particularly small and desired shape can also be produced by the spray-drying technique. It produces free-flowing monodispersible powder. Particles of below 5µm can be prepared by controlled precipitation with the help of ultrasound. This involves ‘shock cooling’ of a hot, saturated solution of the drug in combination with ultrasonic ‘insonation’ of its solvent environment. A number of techniques and tools are utilized to observe particle size and the most extensively used is ‘microscopy’, which is capable of measuring particles of 0.3µm or bigger. Sieving is another method for particles in the 40µm or higher scale. An assortment of instruments based on light scattering, light blockage, or blockage of electrical conductivity is obtainable. The majority of these devices calculate the quantity and dimensions of particles and automatically translate them to weight and size distribution. The most commonly used technique to measure surface area employs the Brunauer, Emmet, Teller (BET) theory of adsorption using an inert gas as an adsorbate at a specific partial pressure (Lierberman et. al. 1996, p.198). 2.7 Side Effects of the chosen formation of the Paracetamol Crystallization processes in pharmaceutical science influenced both the solid-state properties of the drug substance, and the drug product strength and functioning. It should be clear that even slight alteration in crystallization conditions such a supersaturation, temperature, cooling or evaporation rate, and impurity can bring about considerable difference in the crystal properties. These alterations in crystallization parameters can bring about major disparities in the thermodynamic and mechanical properties. These consequences have been distinguished as the leading batch-to-batch deviation problems, resulting to irregularities in the final drug formulation properties (Thompson 2003, p.18). Disparities in crystallization conditions may furthermore present instability upon the product, resulting to disorganized and formless states, polymorphism, chiral separation, or the occurrence of solid-state reactions. Supersaturations can influence crystal growth intensely, consequential to morphological transformation in the crystallizing compound over a range of supersaturations. The quantity of crystals formed grows with supersaturation while the size of crystals shrinks. However, low supersaturations or controlled cooling, as we mentioned earlier produced large crystals and bioavailability of a drug is maintained when supersaturation of a growth medium is controlled (Thompson 2003, p.18). 3. Conclusion Since cooling is appropriate to substances that exhibit strong dependence on temperature, creating the solid phase of aqueous solution through supersaturation with controlled cooling is the best way to manufacture paracetamol. However, most cooling crystallizers are often designed to run so the supersaturation remains almost constants and one operational problem with extensive cooling is that the crystallizer can have scaling at the cooling interface. This also true with the evaporation methods because scaling across the liquid surface can occur due to the concentration of solution at the evaporation surface. Because of the complex nature of crystallization, the theory of crystallization can be best used to troubleshoot and improve the operation of an existing crystallizer. However, Attempts to design a new crystallizer from the theory alone will not lead to the best commercial design thus it is necessary to have experienced crystallizer designers incorporate their knowledge about their equipment and their experience with scaling to achieve the commercial crystallizer designs that will best meet the requirements. 4. Bibliography Amiji Mansoor and Sandmann Beverly. 2002, Applied Physical Pharmacy, McGraw-Hill Professional, U.S. Avis Kenneth, Lieberman Herbert, Banker Gilbert, Rieger Martin, and Lachman Leon. 1996, Pharmaceutical dosage forms: parenteral medications. 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