Trinity College of DublinM.Sc. Pharmaceutical Analysis

TMA: Module 09

Name: Mustafa Hamido

Student Number: 11263930

Tutor Marked Assignment

Module 09

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1. You have been asked to design an oral liquid formulation of ibuprofen for paediatric use.(i) Discuss the issues which should be considered before embarking on the formulation design/manufacturing process. (ii) Give the formula of what you would consider to be a suitable preparation, indicating the role of each constituent of the vehicle in the preparation.

) i) Discuss the issues which should be considered before embarking on the formulation design/manufacturing process

Oral Liquid formulations are solutions, emulsions or suspensions which have one or more active ingredients in a suitable vehicle; some liquids taken orally may contain liquid active ingredients. They are to be swallowed either undiluted or after dilution. They may contain antimicrobial preservatives, antioxidants and other excipients such as dispersing, suspending, thickening, emulsifying, buffering, wetting, solubilising, stabilising, flavouring and sweetening agents and coloring matter authorized by the competent authority ……(1)BPThe main factor to be considered in the preparation of solutions is the solubility of the drug in the required vehicle. The vehicle is usually aqueous but may be oily or alcoholic. Insoluble or sparingly soluble materials may be brought into solution by a number of formulation techniques. These are:

a) Adjustment of pH: if the drug is to be formulated into a liquid product, is adjustment of the pH of the solvent to enhance solubility. However, for many drug substances pH adjustments not an effective means of improving solubility. Weak acidic or basic drugs may require extremes in pH that are outside accepted physiologic limits or that may cause stability problems with formulation ingredients. Adjustment of pH usually has little effect on the solubility of substances other than electrolytes. In many cases, it is desirable to use cosolvents or other techniques such as complexation, micronization, or solid dispersion to improve aqueous solubility.

b) Use of cosolvents such as alcohol or glycerol c) Solubilisation d) Formulation of soluble complexese) Chemical modification f) Particle size reduction: decreasing the particle size may affect on the solubility of the

drug. It might be a slight effect on increasing the solubility of the drug.

The choosing of the solvent is an important factor to be taken in consideration whole preparing oral liquid formulation. The ideal solvent is water, however not all drugs are soluble in water and some drugs are even not stable in the aqueous solutions. Aqueous and viscous aqueous solutions use purified water as the vehicle. Viscous aqueous solutions are sticky, thick, sweet solutions that are either liquid or semisolid. Non-aqueous solutions are those that utilize solvents, or dissolving liquids, in addition to or instead of water. Commonly used non-aqueous solvents include alcohol (ethyl alcohol or ethanol), glycerin, and propylene glycol. Non-aqueous solutions that employ alcohol and their solvent

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are call alcoholic solutions. Hydroalcoholic solutions are non-aqueous solutions that contain a mixture of alcohol and water.

Oral liquid preparations need antimicrobial preservative to prevent the antimicrobial growth during their storage. Other types of preparations that are not sterilized during their preparation but are particularly susceptible to microbial growth because of the nature of their ingredients, preservatives are added to them to protect them. The nature of these Preparations provides excellent growth media for microbes are most aqueous preparations, especially syrups, emulsions, suspensions. Certain hydroalcoholic and most alcoholic preparations may not require the addition of a chemical preservative when the alcoholic content is sufficient to prevent microbial growth. Generally, 15% V/V alcohol will prevent microbial growth in acid media and 18%V/V in alkaline media.

Choosing of the suitable preservative is an important issue to be taken in consideration while preparing oral liquid preparations. The preservative must prevent the growth of the type of microorganisms considered the most likely contaminants of the preparation. It should also be soluble enough in water to achieve adequate concentrations in the aqueous phase of a system with two or more phases. The concentration of the preservative added to the preparation should not affect the safety of the patient when swallowed. It should be also compatible with other preparation ingredients in the preparation and doesn’t affect the preparation container or closure.

Bitterness and taste of drug is also an issue should be discussed in oral preparations. Flavoring agents can be added to the formulation to mask the bitterness of the drug. The flavoring of pharmaceuticals applies primarily to liquids intended for oral administration. The selection of an appropriate flavoring agent depends on several factors, primarily the taste of the drug substance itself. Certain flavoring materials are more effective than others in masking disguising the particular bitter, salty, sour, or otherwise undesirable taste of medicinal agents. Tastes and flavors preferences of people differ, cocoa-flavored vehicles are perceived effective for masking the taste of bitter drugs. Fruit or citrus flavors are used to combat sour or acid-tasting drugs, and cinnamon, orange, raspberry, and other flavors are widely used to make preparations of salty drugs more acceptable by patients.

Some substances are used to enhance the stability of the drug substance, particularly against hydrolysis and oxidation. In each instance, the added pharmaceutical constituent have to be compatible with and must not detract from the stability of the drug substance. There are several approaches to the stabilization of pharmaceutical preparations containing drugs subject to hydrolysis. Perhaps the most obvious is the reduction or elimination of water from the pharmaceutical system. In liquid preparations, water can be replaced or reduced in the formulation through the use of alternative liquids such as glycerin, propylene glycol, and alcohol. Decomposition by hydrolysis may be avoided by suspending them in a nonaqueous vehicle rather than dissolving them in an aqueous solvent.

The age of the patient whether it is designed for pediatrics, geriatrics is an important factor to be aware while preparing oral liquid preparations. Some additives might be problematic

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for children. These additives must be avoided or use them in small amounts for those which are safe in small concentrations. WHO has published a list of examples of excipients which may be harmful and problematic for children.

Table 1 Examples of excipients which may be harmful and problematic for children.

(ii) Give the formula of what you would consider to be a suitable preparation, indicating the role of each constituent of the vehicle in the preparation.

Ibuprofen is prescribed for children for the treatment of acute pain and fever, and for juvenile idiopathic arthritis. The pharmacokinetic characteristics of ibuprofen in children are similar to those in adults and the relationship between dose and response is linear over the range 5-10 mg/kg. The effective dose range to be 7.5-10 mg/kg. The maximum reduction in temperature occurs 3-4 hours after administration. Other clinical trials showed that ibuprofen is effective as or more effective than paracetamol as an analgesic and antipyretic and has a longer duration of action. The adverse effects of ibuprofen are similar to those of other non-steroidal anti-inflammatory drugs and it is safer in overdose in comparison to paracetamol and aspirin.

“Ibuprofen Paediatric 100mg/5ml oral suspension” is a pediatric preparation by Abbot. It is an Orange-coloured and flavoured syrup-like suspension where Each 5ml contains 100mg Ibuprofen and Each 5ml also contains: 5mg methyl parahydroxybenzoate

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(E218), 2.5mg propyl parahydroxybenzoate (E216), 500mg sorbitol solution non-crystallising, (E420), 3.3 g sucrose and 0.5mg sunset yellow FC edicol (E110).

The recommended dose of Brufen for Children is 20 mg per kg of bodyweight daily in divided doses. This can be achieved as follows: a) 1-2 years: 2.5 ml (50 mg) three to four times a day. b)3-7 years: one 5 ml spoonful (100 mg) three to four times a day. c)8-12 years: two 5 ml spoonfuls (200 mg) three to four times a day. The below is the complete list of the excipients added to the preparation:

Each 5ml contains 100mg Ibuprofen Role of the Excipient Methyl parahydroxybenzoate (E218) PreservativePropyl parahydroxybenzoate (E216) PreservativeSucrose SweetenerCitric Acid Monohydrate PreservativeSodium Benzoate (E211) PreservativeAgar BPC '54 Pdr Suspending agent/ emulsifying agentGlycerol (E422) Preservative/Co-solventSorbitol Solution Non-Crystallising (E420) SweetenerIrradiated Light Kaolin Suspending agentPolysorbate 80 Emulsifier/surfactantSunset Yellow FC Edicol (E110) Colouring agentsOrange Flavour D717 Flavouring agentPurified Water

2. Describe the various components of a product to be applied to the skin. Give examples of every group of constituents described.

Drug products topically used on the skin are categorized in two general categories: those are used to achieve local action and those for systemic effects. Local actions include those at or on the surface of the skin, those that exert their actions on the stratum corneum, and those that modulate the function of the epidermis and/or the dermis. Common products in the category that modulate the function of the epidermis and the dermis include creams, gels, ointments, pastes, suspensions, lotions, foams, sprays, aerosols, and solutions. Creams, ointments, and gels generally are referred to as semisolid dosage forms. The most common drug products applied to the skin for systemic effects are referred to as self-adhering transdermal drug delivery systems (TDS) or transdermal patches.

Topical dosage forms include different kinds of preparations. They include solids such as suspensions, emulsions and semisolids such as creams, gels, ointments, .etc. Topical dosage forms include also solid preparations and sprays. The physical characteristics of the topical dosage forms differ widely. The preparations applied on the skin contain many ingredients.

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1 Dermal Layers

Its constituents depend on the characteristic of the preparation is prepared. These preparations Should/can contain one of the following:

a- Base(simple or compound basis):

Selection of the base depends on the degree of skin penetration. It can be Epidermic (for external products and it has a very little skin penetration) or Endodermic (for internal products and its penetration is into the dermis) or Diadermic (the penetration is into the skin). Bases categorized into four general classes: hydrocarbon bases, absorptionbases, water-removable bases, and water-soluble bases.

Hydrocarbon bases, known also as ‘‘oleaginous ointment bases,’’ are represented by White Petrolatum and White Ointment (both USP). These bases can incorporate only small amounts of an aqueous component. Hydrocarbon bases serve to keep medicaments in prolonged contact with the skin and act as occlusive dressings. These bases are difficult to wash off and.

Absorption Bases may be divided into two groups: the first contains the bases that allow the incorporation of aqueous solutions with the formation of a water-in-oil emulsion (e.g., Hydrophilic Petrolatum and Lanolin, both USP), and the second group consists of water-in-

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oil emulsions that allow the incorporation of more quantities of aqueous solutions (Lanolin, USP).

Water-removable bases are oil-in-water emulsions (e.g., Hydrophilic Ointment,USP), and are called ‘‘creams’’ .They also are known as ‘‘water-washable’’ because they can be easily washed from the skin or clothing with water. This advantage makes them more acceptable for cosmetic industry. Other advantages of the water removable bases are that they may be diluted with water and that they favor the absorption of serous discharges in dermatological conditions.

Water-soluble Bases so-called ‘‘greaseless ointment bases’’ comprises water-soluble constituents. In addition to the advantages of water-removable bases, this type contains no water-insoluble substances such as petrolatum, anhydrous lanolin, or waxes. They are more correctly called Gels.

a- Emulsions are stabilized by emulsifying agents that prevent coalescence, the merging of small droplets into larger droplets, and, ultimately, into a single separated phase. Emulsifying agents (surfactants) act by concentrating at the interface between the immiscible liquids, thereby providing a physical barrier that reduces the tendency for coalescence. The active constituents which can be one or more active compounds. A widely known example of emulsifiers is wool alcohol.

b- Antimicrobial preservatives are added to help improve antimicrobial stability and hence requiring antimicrobial activity. Their presence is mandated for multidose liquid and semi-solid products and performance standards

Table 2 Preservatives used in oral liquid preparations

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Preservatives don’t provide protection against viral contamination. Preservative system protects the product against microbial proliferation but does not compromise product performance. There are a limited number of regulatory approved preservatives that can be included in the multi-use topical products.

c- Antioxidant such as Vitamin E should be included whenever there is a possibility of oxidative degradation of the base. It may be added as a combination of two antioxidants instead of one. The concentration of antioxidants would depend upon their partition coefficients between the aqueous and oily phases if both the phases are present in a base.

d- Viscosity of the preparation is increased by adding thickening agents. Thickening agents are usually used in combination with emulsifier. They are used to modify the rheology of water-based systems and to stabilize multi-phase systems such as

emulsions and suspensions. Carbopol®* polymers, Pemulen™* polymers and Noveon®* polycarbophil are widely used excipients for thickening lotions, creams and gels.

e- Penetration enhancer such as DMSO is also can be added to the topical preperations. Dimethyl sulfoxide (DMSO) is a molecule with a long history in pharmaceutics and is now well established as a penetration enhancer in topical pharmaceutical formulations. Penetration enhancers are added to enhance the drug permeation through skin. Penetration enhancer should be non-toxic, non-irritating and no allergenic.

3. Which drug characteristics would you consider to be of importance when formulating solid dosage forms such as capsules and tablets?

The tablet dosage form accounts for approximately 50% of all dosage forms in the market. Tablets have many advantages over other dosage forms. They are delivering the accurate dosing and have good physical and chemical stability. And they are Competitive in their production costs with high level of patient acceptability and convenience. Few problems are facing the tablets dosage forms. These problems are perceived as the major disadvantages of the widely used dosage form. Some drugs are not able to be compressed, others have irritant effect on the GIT and some are poorly soluble which may affect on the bioavailability and lead to bioavailability problems resulting from slow disintegration and dissolution.

Choosing excipients is important step in the development of the optimum tablets. Excipients determine the bulk of the final product in dosage forms such as tablet, capsule, etc., the speed of disintegration, rate of dissolution, protection against moisture, and stability during storage, and compatibility.

Excipients should not be chemically active, no reaction with the drug substance, no influence on other excipients, and shouldn’t increase the chance of microbial growth.

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Diluents increase the volume to a formulation to prepare tablets of the desired size. Examples of fillers are lactose, dextrin, and microcrystalline cellulose

The selection of fillers depends on various factors, such as the experience of the manufacturer in the preparation of other tablets, its cost, and compatibility with other formulation ingredients.

Many drugs are not able to be compressed. Binders enhance the adhesion of particles of the formulation. This adhesion enables preparation of granules and maintains the integrity of the final tablet.

Table 3 some examples of binders

Lubricants are kind of excipients which are reducing or preventing friction and heat when introduced as a film between solid surfaces. It works by coating on the surface of particles, and consequently preventing adhesion of the tablet material to the dies and punches during manufacturing. Glyceryl monostearate is one example of a lubricant.

The role of the Lubricants which are playing in the preparation of tablets are :

1. Improving the flow of granules in the hopper to the die cavity.

2. Preventing sticking of tablet formulation to the punches and dies during formulation.

3. Reducing the friction between the tablet and the die wall during the tablet’s ejection from the tablet machine.

4. Giving shine to the finished tablets.

Glidants are excipients which allow particles to move smoothly, continuously, and effortlessly. Both lubricants and glidants have the same effect, however, the differ in the way they are working. Unlike lubricant, glidant remove moisture and as a result enhancing flow.

Drug absorption depends on the drug in the dissolved state. The dissolution property is a major issue for bioavailability. If the rate of dissolution is lower than the rate of absorption (i.e., if the rate of dissolution is the rate-limiting step), then the dissolution rate determines the bioavailability. The therapeutic effect of different formulations of the same drug depends on the rates at which the drug is released.

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The breakup of the tablets to smaller particles is important for dissolution of the drug and subsequent bioavailability. Disintegrating agents increase such breakup. To breakup of tablets, disintegrating agents must swell or expand on exposure to aqueous solution. The most effective disintegrating agents are those which have the highest water uptake.

Table 4 Disintegrating agents

In general, the more hydrophilic, the better disintegrating agents. If a drug is not highly water soluble, the dissolution will decrease and will affect on the bioavailability of the drug. A number of techniques can be used to increase the dissolution rate. For compounds with limited solubility (0.1 mg/mL or less), decreasing the particle size increases the absorption. If the solubility of a drug is 1 mg/mL or less, then changing the size of the drug particles will increase the surface area and consequently will increase the absorption and dissolution rate. Other techniques will increase the solubility of the drug such as formation of salt forms from the acid or base form of the drug ,Choice of anhydrous or hydrate form ,Change in crystal form of polymorphs ,Increase in surface wettability, Use of hydrotropic agents and Formation of solid dispersion.

The first step toward dissolution of a tablet is wetting of the surface. If the surface of a tablet is not hydrophilic enough to permit water to spread and absorbed into the tablet, dissolution will not take place or will take a long time and the bioavailability will be decreased. Various wetting agents can be used can be added to increase wetting. A wetting agent is a surfactant (i.e., surface active agent) which allows easy spreading of water on the surface. In addition, It makes water easy to displace air and spread over the surface inside the tablet. The release of a drug from the tablets can be controlled by including polymeric materials. The polymers are used mainly in the design of sustained release tablets.

Compressed tablets can be coated with a sugar layer. Sugar layer is water-soluble. It is quickly dissolved in aqueous environment .The main purposes of having a sugar coating are:

(1) To protect the drug from the air and humidity

(2) To provide a taste or a smell barrier to objectionable tasting or smelling drug

(3) To enhance the appearance of compressed tablets.

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Compressed tablets can be coated also with a thin layer of a polymer, which may be either water-soluble or water-insoluble. The polymer film has an advantage over sugar-coating in that the polymer film is more durable, less bulky, and less time-consuming to apply. The polymer film may remain intact or dissolve in the GI tract depending on the water-solubility when the tablet administered orally. Of the many water-soluble polymers, some polymers show the property of pH-dependent water-solubility. Some polymers do not dissolve at low pH (e.g., pH in the stomach) but readily dissolve at neutral pH (e.g., pH in the intestine). If such a polymer film is coated on compressed tablets, the tablets will resist dissolution or disruption in the stomach but not in the intestine. Such tablets are known as enteric-coated tablets. Since enteric-coated tablets do not dissolve in the stomach, they are useful for the drugs which are not stable in stomach i (i.e., at low pH) or which are irritating to the gastric mucosa.

Tablets should be made sufficiently hard to resist breaking during packaging, shipment, and normal handling. Tablets should be soft enough to disintegrate and dissolve properly after administered.

Tablets may be imprinted with a symbol of the manufacturer to denote the company, the product, or both. To make imprinted tablets punches having impressions are used. Punches with raised impressions will produce recessed (embossed) impressions on the tablets, and vice versa.

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References:

Handbook of Pharmaceutical Excipients. S I X T H E D I T I O N Edited by:

1. Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MInstP o Chief Scientist o Intelligensys Ltd, Stokesley, North Yorkshire, UK

2. Paul J Sheskey BSc, RPh o Application Development Leader o The Dow Chemical Company, Midland, MI, USA

3. Marian E Quinn BSc, MSc o Development Editor o Royal Pharmaceutical Society of Great Britain, London, UK

http://www.americanpharmaceuticalreview.com/Featured-Articles/38886- Antimicrobial-Preservatives-Part-One-Choosing-a-Preservative-System/

Int J Clin Pract Suppl. 2003 Apr;(135):9-12. : A general overview of the use of ibuprofen in paediatrics. Autret-Leca E . Tours University Hospital, France. http://www.ncbi.nlm.nih.gov/pubmed/12723740

Phys Sportsmed. 2011 Sep;39(3):75-82. doi: 10.3810/psm.2011.09.1923.: Dimethyl sulfoxide: an effective penetration enhancer for topical administration of NSAIDs. Marren K . karrie.liuchan@covidien.com

A Review of Medication Dosage Forms, Drug Administration, Pharmacokinetics, and Abbreviations. A Knowledge Based Course For Technicians By Jeff Blackburn, MBA – Healthcare Administration, C.Ph.T.

Report for WHO on findings of a review of existing guidance/advisory documents on how medicines should be administered to children, including general instructions on compounding preparations and manipulation of adult dosage forms by by Dr T. Nunn, United Kingdom for Dr S. Hill, Medicines Access and Rational Us and Secretary, WHO Expert Committee on the Selection and Use of Essential Medicines

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