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Protocols for Extemporaneous Preparation

Investigating the ease of identifying drug concentrations of extemporaneously prepared sertraline.

Drug formulation consist of active ingredient and excipient. The proper design and formulation of dosage form requires proper standards of preparing formulation which include physical, chemical and biological characteristics. The active ingredient must be compatible with excipients and preservative in order to prepare stable formulation. In absence of licence drug, pharmacist prepare formulation with proper guidelines referred by drug regulatory bodies. These formulation are referred as extemporaneously prepared formulations. Stewart and Tucker surveyed that 116 drugs were extemporaneously prepared in Australian hospitals by pharmacists for paediatric use. The major problem associated with extemporaneously prepared formulation is unpleasant taste and lack of stability. Clinical data associated with these problems is not easily available in the research article. Adverse events were not reported which linked with extemporaneously prepared formulation.

An extemporaneous preparations should be used only when commercial product is not available and where you can prepare the product in compliance with accepted standards. Before starting preparation of extemporaneous products, some protocol should be followed by the pharmacies. Competent staff should be used to undertaken the task to be performed in the laboratory. Requisite facility and equipment’s must be available for preparation of the extemporaneous products. Proper safety measures should be taken while preparing the product. Ingredients must be taken from recognised pharmaceutical manufacturer and quality of the product must be maintained as per usage in preparation and manufacturing of product. Proper handling techniques must be considered while using hazardous products so that any risk related to substance can be avoided. Product should be properly labelled as per labelling guidelines which includes manufacturing date, expiry date, proper use of product, safety measures and storage of the product where preparation is dispensed, patient and prescription details, date of dispensing and pharmacist involved in preparation.

Extemporaneous preparations have been associated with quality defects, infectious disease outbreaks. Federal surveillance requirements are not available, hence quality and safety of compound is unknown. Limitations of Extemporaneous preparations includes the risk of non-standardised formulations, non-uniformity in dosing, microbiological contamination and a lack of stability in formulation.

Pharmacies are not required to report adverse events related to extemporaneous preparations, the risk extent of compounded drug associated with morbidity and mortality cannot be assessed.

Extemporaneous preparations in the pharmacies are at low quality assurance and at highest risk whereas licensed drugs manufacturers provide most robust quality assurance, efficacy and safety. Unlicensed drugs has cheaper cost than licensed drugs, because of low quality assurance and risk. Most unlicensed drugs are manufactured under ‘special license’ represents intermediate level of quality and risk. The only difference between licensed and special drugs is that license drugs has evidence for pharmaceutical quality, safety and efficacy in clinical use whereas special drugs is much weaker and is not subjected to regulatory assessment. The study was conducted in U.S. in which unlicensed drugs were prescribed by doctors to outpatient’s teens. The study evaluated that as licensed drugs are expensive and for above 18 years, therefore sertraline extemporaneous products prepared from unlicensed drugs were given to most teen outpatient.

Limitations of Extemporaneous Preparations

Doctors may prescribe a cheaper off labelled alternative medicine, as long as this medicine is approved by the authoritative clinical guidelines and it is as effective as licenced version.

The study was conducted to search new off labels indications for off labels drugs for psychotropic drugs. The efficacy of three dose levels sertraline compared with placebo in the treatment of nondepressed adults outpatient with obsessive compulsive disorder. A significant improvement was seen with patient in the sertraline group with 50 mg and 200 mg dose as compared to placebo group. The FDA approved sertraline for the treatment of OCD in 1997 (Bazzano, 2009).

Sertraline was approved by FDA in 1991 on the recommendation of psychopharmacological drug advisory committee. In 2002, FDA approved sertraline for children aged from 6 yrs to older for OCD. In 2005, FDA added black box warning concerning paediatric suicidal behaviour.

Problems related to extemporaneous products are chemical instability, microbiological instability and physical instability. Extemporaneously prepared liquid formulations mainly are susceptible to chemical reaction leading degradation. Microbial growth in oral liquid formulation may cause foul odour, turbidity and adversely affect palatability and appearance. Extemporaneously prepared oral suspension are susceptible to suspension and this lead to sedimentation of insoluble drug.

Chemical instability:

Drugs in extemporaneously prepared may be susceptible to chemical reaction such as hydrolysis, oxidation and reduction and leads to degradation. Factors which may increase the rate of chemical reaction includes presence of trace metals which catalyse the oxidation. The rate of chemical degradation increases with increase in temperature.

Microbiological instability:

Microbial growth in an oral liquid may cause foul odour, turbidity and adversely affect palatability and appearance. By products of microbial metabolism changes pH, decrease chemical instability and solubility of drugs.

Physical instability:

Extemporaneously prepared drug suspension capable of causing sedimentation of insoluble drugs, thus forming caking. Difficulty in re-suspending the drug after shaking may cause wrong distribution of drug in the vehicle and causes erratic dose measurement.

Unlicensed medications are prescribed by the doctors and is known as specials in the industry. They are specially formulated for a specific patient needs and that is why they are unlicensed. Thus, there is no commercial interest. Specials extemporaneous products formulate in the industry, when drug is available in the tablet form and need to be formulated in the liquid form. Manufacturing of unlicensed drugs under the manufacture of special licence drugs is called special drugs. These drugs have intermediate quality and safety in comparison to licence products. But much better quality assurance and less risk assessment than extemporaneous formulation.

The technical and clinical risk associated with extemporaneous preparations are:

Formulation failure:

The causes if formulation failure are numerous and can be complex, including physical incompatibilities, drug/excipient binding issues, drug degradation.

Calculation error:

Common calculation errors associated with extemporaneous preparations include converting units one to another (e.g. mg to µg or conversion from weights in volumes to millimoles). Calculation errors leads to 1000 folds overdose (Kirsch, 2005).

Starting materials:

All staring material mainly those of animal origin, should be certified free from TSE. Care should be taken with the use of carcinogenic sugars such as sucrose in paediatric formulations as it has been associated with dental cavities.

Unlicensed Drugs

Health and safety risks:

The risk to the operator should be considered. A control risk assessment should be carried out and any risk should be identified and evaluated before undertaking extemporaneous preparations.

It is recognized that extemporaneous pediatric formulations are not ideal. European Union in 2006, approved laws for companies to do the necessary research in children. Due to amendment of these laws, new scientific data has been generated for the appropriate usage of medications in children. The appropriate formulation allows children to participate in clinical trials for dose finding, efficacy and safety. Children has very heterogeneous population that includes newborns, infants, toddlers, preschoolers, school-age children, and adolescents. Therefore, different formulations are need to be developed with same active ingredient for appropriate testing in clinical trials.

The preparations procedure includes all practical processes required for extemporaneous prepare, package, labelling, and ready to supply to assign patient. The processes includes prescription verification, worksheet and label generation, assembly of components, weighing, measurements of liquids, grinding tablets into uniform powders, mixing, reconciliation and packaging and labelling.

Due shortage of data available, pharmacist faced many problems related to extemporaneous product may not find a proper validated formula. In absence of publishing data, pharmacists should considered taking advice from quality assurance pharmacist or other personnel expert in preparing extemporaneous formulations. Considering stability issues following hints should be kept in mind such as:

Shelf life:

It is recommended that extemporaneous product should not be stored for more than 28 days if preserved and 7 days if unpreserved.

Dosage form:

The choice of dosage should be depend on the clinical situation and also the patient (such as age, ability to swallow).

Drugs in extemporaneously prepared may be susceptible to chemical reaction such as hydrolysis, oxidation & reduction which leads to degradation. Factors which may increase the rate of chemical reaction includes presence of trace metals which catalyse the oxidation. The rate of chemical degradation increases with increase in temperature.

Excipient are expected to be pharmacologically inactive. All sweeteners containing sucrose and fructose may affect blood sugars, sorbitol and xylitol may cause osmotic diarrhea. Propylene glycol is commonly used as a solvent in oral, topical and injectable drugs. Patient aged less than 4 yrs. may accumulate propylene glycol due to decreased metabolism. Extemporaneous preparations without sufficient preservatives are more subtle to microbial contamination.

Quality assurance of extemporaneously prepared pharmaceuticals is of prime importance. Quality system should include all aspects of quality assurance and good preparation practice. It should describe the quality policy, should state scope of pharmaceutical quality system, should assess risk assessment, include process performance and quality monitoring, and policy and procedures for corrective and preventive actions. It should also include testing of stability, potency and sterility and safety consideration of excipients (Lowey A. and Jackson M., 2008).

One time dose of medication with preservative showed no toxicity risk in even premature neonates (McRorie, 1996). Multiple dose of medication with preservatives caused life threatening toxicity in neonates. The USFDA reported 16 death associated with benzyl alcohol in neonates which are caused from benzyl alcohol syndrome, the normal metabolic pathway for benzyl alcohol in adults are immature in premature neonates, thus leading to accumulation of benzyl alcohol (Brown, 1982). Ethanol caused CNS depressant, use of sucrose in formulations causes dental carries if used for long times. The examples discussed need to be used with extra care in preparing extemporaneous formulations particularly in case of children.

Off Label Medicines

When preparing extemporaneous drugs, shelf life of product should considered. Shelf life can be increased with proper use preservatives, which can increase stability of extemporaneous products. Selection of preservative should be based on various factors such as:

Inhibit growth of microorganism, should be water soluble, not be in dissociated form, non-irritating and non-sensitizing, should be compatible with other active ingredients and should have adequate stability.

Preparation of extemporaneous formulation in case of paediatric is based on experience rather than data from specific stability and sterility study. Published clinical studies in paediatric patient lack of dosage form and more than 20% articles lack to provide formulation used in the study.

Bioavailability and pharmacokinetic studies are rarely conducted for extemporaneous products. This is due to lack of financial resources and complexity of study conducted at healthcare premises. Thus, treatment involving extemporaneous products observed their efficacy and tolerability in patient.

According to USP compounding standards, adverse events related to extemporaneous formulation should be reported to USP MEDMARX program. Some state board stated to report adverse event in FDA Medwatch program, but none of these programs are mandatory for reporting adverse events from extemporaneous products, but are related to handle adverse events from manufacturing drug products.

Extemporaneous products are not generally evaluated by controlled trials to establish effectiveness and tolerability in patients. As these studies are very expensive than bioavailability and pharmacokinetic studies, thus cannot be conducted by majorly extemporaneous products. Patient receiving extemporaneous products, should be monitored assure effectiveness and tolerability.

Therapeutic needs children are sufficiently different from those of adult. According to American society of paediatric, many children have been treated with medications which have no sufficient information also called off label drugs. Therefore, it has been seen that use of extemporaneous formulation and off label drugs are nor ideal. As paediatric drug development is now integral part of the development of new drug. Initial clinical testing need to be done in adult to demonstrate acceptable bioavailability and palatability. Once formulation is chosen, initial clinical study are done on children, once safety and efficacy of formulations are demonstrated.

Lack of safety information in relation to geriatric extemporaneous drugs is major problem. Specific clinical data related to formulation for geriatric patient is missing in the research articles. In recent survey it was found that geriatric extemporaneous formulations data is missing in many renounced journals. Adverse events related to geriatric population does not filed.

Sertraline is an antidepressant, belong to selective serotonin reuptake inhibitor class. It was introduced by Pfizer in 1991. It is primarily prescribed for major depressive disorders and obsessive compulsive, panic and social anxiety to children and adults. It is also effective for the treatment of social phobia and post traumatic disorders.

Chemical name of sertraline is (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine.

The inactive ingredients of sertraline are dibasic calcium phosphate dihydratehydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide.

Chemical and physical properties:

Sertraline has mol. Wt. 306.22g/mol. It has molecular formula C17H17Cl2N with melting point 243-245ºC. Water solubility is 3.5mg/L.

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Pharmokinetics (ADME) /pharmodynamics

A study was conducted to determine the pharmacokinetic and pharmacodynamics properties of sertraline. It is found that sertraline is absorbed readily through the GI tract. It comes in first order kinetics. Maximum plasma concentration reached in 4-8.4 hr. Serum levels are in steady state at 10-120 ng/mL of sertraline & its desmethyl metabolites. Plasma protein binding is extensive (up to 98%) to both albumin & alpha1-acid glycoprotein. Distribution of oral administered sertraline is biphasic with a prolonged absorption phase. The elimination phase begins 12-16 hrs. after the administration of drug. The volume of distribution has not been determined in humans but it is found that in rats it is more than 20 L/kg. Sertraline and its metabolites exhibit extensive distribution into tissues outside the blood. The elimination half-life of sertraline in humans is 24-25 hr. The clinically active desmethyl metabolite is eliminated more slowly than the parent drug with a half-life of approximately 66 hr. Unchanged sertraline is not detected in the urine.

Side effects of sertraline are mild agitation, mild sedation, moderately to severe GI effects and moderate to severe sexual effects (Hardman, 1996).

Physiochemical properties:

Sertraline has melting point 245ºC. Water solubility is 3.5mg/L. It is soluble in DMSO. The pharmacokinetic properties of sertraline are confirmed by physiochemical properties. In the study it was found out that sertraline has 9.16 logK value which indicates that the molecule is present mainly in the ionized (BH+) form in different compartments of the human body. Inonized state of GI tract is unfavourable to the absorption of sertraline which is balanced by high lipophilicity of sertraline. The ΔlogP value of sertraline is equal to zero which indicates the lack of H-bond formation and explains its high brain concentration (Deak, 2008).

A study was developed for the determination of degradation of sertraline. The spectrophotometric method was extended to stability study of sertraline. The drug was exposed to acidic, alkaline and oxidative and photolytic degradation. Oxidative degradation of drug was determined and with first order of rate of reaction (Deak, 2008).

Each mL of oral solution contains sertraline hydrochloride equivalent to 20 mg of sertraline. Other inactive ingredients are glycerine, alcohol, menthol and butylated hydroxytoluene (BHT). The oral concentrate must be diluted prior to administration.

Sertraline show dangerous interaction with MAO inhibitors (particularly long-acting MAO inhibitors).The resulting reactions referred as "serotonin syndrome". This syndrome typically includes restlessness, muscle twitches and myoclonus, hyper reflexia, sweating, penile erection, shivering and tremor with seizures & coma. The reaction is often self-limiting if the diagnosis is made quickly & the offending agents are discontinued (Hardman, 1996).

Sertraline is a selective 5-HT reuptake inhibitor. Sertraline through inhibition of 5-HT release, may cause beta-adrenoceptor down regulation. The exact mechanism of action sertraline is not fully known, but it selectively inhibit the reuptake of serotonin at the presynaptic membrane. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. According to given hypothesis, it has been found that obsessive-compulsive disorder is caused by the dysregulation of serotonin, as it is treated by sertraline which results in correcting the balance (Ellenhor, 1997).

A study was conducted on formulation and evaluation of fast dissolving buccal films of sertraline. In this study, the buccal films were prepared from polymers such as polyvinyl pyrrolidone, carbopol 934P in different ratios by solvent casting method. Propylene glycol or PEG 400 as plasticizers and mannitol or sodium saccharin as sweeteners. This formulation was evaluated by in-vitro drug release studies by USP dissolution apparatus and experimental data showed that this buccal film formulation release 90-95% sertraline drug in one hr.

A study was conducted on the formulation development of sertraline hydrochloride micro emulsion for intranasal delivery. Objective of this study was to improve solubility of sertraline hydrochloride (STH) and then to formulate micro emulsions containing STH to accomplish rapid onset of action and to bypass the first-pass metabolism. Nasal absorption of micro emulsion sertraline drug was found to be 66-67% in in-vitro study. These results showed that sertraline micro emulsion is useful in depression.


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