PHA311 Liquid Dosage Forms (24-25) MOT 7 PDF

PHA311 (24-25)-MOT 7 LIQUID DOSAGE FORMS SOLUTIONS AND OTHER LDF’S 2024/10/13 55 1 Contents Liquid Dosage Forms Types of Liquid Dosage Forms Solutions Definitions Classification of Solutions Absorption of drugs in solution form Adv...

PHA311 (24-25)-MOT 7 LIQUID DOSAGE FORMS SOLUTIONS AND OTHER LDF’S 2024/10/13 55 1 Contents Liquid Dosage Forms Types of Liquid Dosage Forms Solutions Definitions Classification of Solutions Absorption of drugs in solution form Advantages And Disadvantages of Solutions as an Oral Dosage Form Advantages Disadavantages 2024/10/13 55 2 Contents (Cont.) Solutions – Solubility General rules of solubility Relative Terms of Solubility Some Solvents for Liquid Preparations Purified water USP – Preparation Ion exchange Method Aqueous solutions Choice of solvent Solubilisation Non-aqueous Solutions Other formulation additives Oral Liquid Dosage forms Contents (Cont.) The International Pharmacopoeia - Ninth Edition, 2019 on Liquid Preparations for Oral Use Formulation Components And Manufacturing Process Manufacturing Process Preparation of Solutions Clarification of solutions Packaging and Storage of Pharmaceutical Solutions Quality Attributes Types of preparations Other Oral Liquid Dosage forms 2024/10/13 55 4 Liquid dosage forms Dosage forms are essentially pharmaceutical products in the form which involves a mixture of active drug components and nondrug components (excipients). Liquid dosage forms are a Liquid form of a dose of a drug used as a drug or medication intended for administration or consumption. 2024/10/13 55 5 Types of Liquid Dosage Forms (by Preparation) Liquid dosage forms are prepared: a. By dissolving the active drug substance in an aqueous or non- aqueous (e.g. alcohol, ether, glycerin) solvent, b. By suspensing the drug in appropriate medium, or c. By incorporating the drug substance into an oil or water phases. 2024/10/13 55 6 2024/10/13 55 7 Types of LDF: By Administration Liquid dosage forms can be administered: a. Topically - lotions or suspension applied to the skin, nasal drops, ear drops, eye solutions. b. Orally (p.o.) – oral suspensions, emulsions, solutions and mixtures. c. Parenterally - subcutaneous injection (s.c.), intramuscular injection (i.m.) intravenous administration (i.v.) 2024/10/13 55 8 Types of Liquid Dosage Forms : by Phases Single Phase (Monophasic) – solutions and mixtures Biphasic (suspensions and emulsions) Multi phase 2024/10/13 55 9 2024/10/13 55 10 2024/10/13 55 11 Advantages of LDF a. Better for patients who have trouble swallowing expiration than other. b. Faster absorption than solids. c. More flexibility in achieving the proper dosage of medication. d. Palatable. e. Best choice for children and old age person. 2024/10/13 55 12 Disadvantages of LDF a. Shorter life than other dosage form, b. Harder to measure accuracy, c. Need special storage condition. d. Less stable, e. Easily affected by microorganisms, f. Bulky to carry around. g. Easy to loss by the breakage of the container. h. Measuring dose is required. 2024/10/13 55 13  SOLUTIONS 2024/10/13 55 14 Definitions Solutions are liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents 2024/10/13 55 15 Classification of Solutions According to their pharmaceutical use oral, otic, ophthalmic, or topical. 2024/10/13 55 16 Classification of Solutions According to their composition or use or preparation Syrups - aqueous solutions containing a sugar (some syrups may contain some alcohol, to aid in the dissolving of the active ingredient), Elixirs – sweetened hydroalcoholic solutions (made with a combinations of water and ethanol) Spirits – solutions of aromatic materials in alcoholic Aromatic waters –aqueous solutions of aromatic materials Tinctures - Solutions prepared by prepared by extracting active constituents from crude drugs or solutions of chemical substances dissolved in alcohol or in a hydroalcoholic solvent. Fluidextracts – are also tinctures Liniments – 2024/10/13 55 17 Absorption of drugs in solution form Absorption of drugs in solution form is quicker absorption of a drug in a solution form from the gastrointestinal tract into the systemic circulation may be expected to occur more rapidly than from suspension or solid dosage forms of the same medicinal agent. 2024/10/13 55 18 ADVANTAGES AND DISADVANTAGES OF SOLUTIONS AS AN ORAL DOSAGE FORM ADVANTAGES easier to swallow than solids immediately available for absorption faster therapeutic response than if using a solid dosage form uniform distribution of drug throughout the preparation (unlike when in suspension form) reduced irritation and damage of the gastric mucosa by the drug because administration of a solution of a drug will result in the immediate dilution by the gastric contents. DISADVANTAGES bulky and therefore inconvenient to transport and store fragile, if should break the whole of the product is immediately and irretrievably lost. poor stability provide suitable media for the growth of bacteria accuracy of dosage depends patient skill to draw a recommended volume Unpleasant taste of drug would be more pronounced  Solutions Solubility 2024/10/13 55 22 2024/10/13 55 23 Solubility The ability of a solvent to dissolve organic as well as inorganic solutes depends on its effectiveness in overcoming the electronic forces that hold the atoms of the solute together and the corresponding lack of resolute on the part of the atoms themselves to resist the solvent action. During dissolution, the molecules of the solvent and the solute become uniformly mixed, and cohesive forces of the atoms are replaced by new forces as a result of the attraction of the solute and solvent molecules for one another 2024/10/13 55 24 General rules of solubility Page 400 Ansel’s 10th edition Inorganic solutes Ionic compound having both the cation and anion monovalent– Generally highly soluble in water (e.g., NaCl, LiBr,KI, NH4NO3, and NaNO2). Only one of the two ions in an ionic compound is monovalent - Generally soluble. (e.g., BaCl2, MgI2, Na2SO4, and Na3PO4). Both the cation and anion are multivalent – Generally poorly soluble in water (e.g., CaSO4, BaSO4, and BiPO4; exceptions: ZnSO4, FeSO4). Common salts of alkali metals (e.g., Na,K, Li, Cs, and Rb) are usually water soluble (exception: Li2CO3). 2024/10/13 55 25 General rules of solubility Ammonium and quaternary ammonium salts are water soluble. Nitrates, nitrites, acetates, chlorates, and lactates are generally water soluble (exceptions: silver and mercurous acetate). Sulfates, sulfites, and thiosulfates are generally water soluble (exceptions: calcium and barium salts). Chlorides, bromides, and iodides are water soluble (exceptions: salts of silver and mercurous ions). Acid salts corresponding to an insoluble salt will be more water soluble than theoriginal salt. Hydroxides and oxides of compounds other than alkali metal cations and the ammonium ion are generally waterinsoluble. 2024/10/13 55 26 General rules of solubility Sulfides are water insoluble except for their alkali metal salts. Phosphates, carbonates, silicates, borates, and hypochlorites are water insoluble except for their alkali metal salts and ammonium salts. 2024/10/13 55 27 General rules of solubility Organic Molecules Molecules having one polar functional group are usually soluble to total chain lengths of five carbons. Molecules having branched chains are more soluble than the corresponding straight-chain compound Water solubility decreases with an increase in molecular weight. Increased structural similarity between solute and solvent is accompanied by increased solubility. 2024/10/13 55 28 General rules of solubility Water solubility decreases with an increase in molecular weight. Increased structural similarity between solute and solvent is accompanied by increased solubility. 2024/10/13 55 29 Relative Terms of Solubility Descriptive Term Parts of Solvent Required for 1 Part of Solute Very soluble 10,000 or insoluble 2024/10/13 55 30 Some Solvents for Liquid Preparations Diluted Alcohol NF, - prepared by mixing equal volumes of Alcohol, USP, and Purified Water, USP. Rubbing Alcohol - contains about 70% ethyl alcohol by volume, the remainder consisting of water, denaturants with or without colour additives and perfume oils, and stabilizers. Glycerine, USP (Glycerol), CH2OH·CHOH·CH2OH - clear syrupy liquid with a sweet taste, miscible with both water and alcohol. Has preservative properties. Isopropyl Rubbing Alcohol - about 70% by volume isopropyl alcohol, the remainder consisting of water with or without colour, additives, stabilizers, and perfume oils. Propylene Glycol, USP, CH3CH(OH) - CH2OH - viscous liquid, is miscible with water and alcohol. Frequentlysubstituted for glycerin Purified Water, USP, H2O – Dissolves most substances 2024/10/13 55 31 Purified water USP – Preparation Distillation method Ion exchange Reverse Osmosis 2024/10/13 55 32 Ion exchange Method Cation exchanger column – resin Anion exchanger column – resin 2024/10/13 55 33 Ion exchange Method- Advantages No heat required Ease of operation/very simple to operate Ease of maintenance Easy to relocate 2024/10/13 55 34 The process of Ion-Exchange Used for water purification, Rapid and reversible process in which impurity ions present in the water are replaced by ions released by an ion-exchange resin The impurity ions are taken up by the resin, Resin must be periodically regenerated to restore it to the original ionic form. 2024/10/13 55 35  The process of Ion-Exchange 2024/10/13 55 36 Ion An ion is an atom or group of atoms with an electric charge. Positively-charged ions are called cations and are usually metals; negatively-charged ions are called anions and are usually non-metals 2024/10/13 55 37 Resins The resins are in the form of insoluble, porous, spherical beads, approximately 0.5mm in diameter. 2024/10/13 55 38 2024/10/13 55 39  Ion-exchange resin An ion-exchange resin or ion-exchange polymer is an insoluble matrix normally in the form of small beads, usually white or yellowish, fabricated from an organic polymer substrate. The beads are typically porous, providing a high surface area. The trapping of ions occurs with the accompanying releasing of other ions; thus the process is called ion-exchange. There are multiple types of ion-exchange resin. Most commercial resins are made of polystyrene sulfonate. Ion-exchange resins are widely used in different separation, purification, and decontamination processes. The most common examples are water softening and water purification. In many cases ion-exchange resins were introduced in such processes as a more flexible alternative to the use of natural or artificial zeolites. Also, ion exchange resins are highly effective in the biodiesel filtration process. 2024/10/13 55 40  A typical ion exchange configuration 2024/10/13 55 41 Ion - exchange Purification Process Video https://www.youtube.com/watch?v=1q9HP0oua_A 2024/10/13 55 42  CHOICE OF SOLVENT Aqueous solutions 2024/10/13 55 43  Approaches to the improvement of aqueous solubility 2024/10/13 55 44 Approaches to the improvement of aqueous solubility Cosolvency pH control Solubilization Complexation Chemical modification Particle size control 2024/10/13 55 45 Solubilisation Solubilisation Oral solution and elixir formulations can be simple or they can be quite complex, involving many types of excipients including water- soluble organic solvents, water-insoluble organic solvents, surfactants, buffers, sugars, flavors, sweeteners, aromatics, dyes, and with/without water Organic cosolvents are normally used to solubilize poorly water- soluble drugs to the desired concentration in oral solutions Surfactants and Cosolvents Surfactants are commonly used in the dosage form to provide an amphilic character to the aqueous vehicle and/or associate with the hydrophobic drug to increase its solubility. When used above their critical micelle concentration (CMC), the surfactants tend to form micelles with hydrophobic parts of the molecule buried inside and the hydrophilic part on the outside, facing the aqueous environment. This allows the partition and retention of hydrophobic drug in the core of the micelle, thus increasing total drug solubility. common examples of surfactants: Soaps (free fatty acid salts) Fatty acid sulfonates (the most common of which is sodium laryl sulfate, or SLS) Ethoxylated compounds, such as ethoxylated propylene glycol. Lecithin. Polygluconates Co-solvents Co-solvents Increase drug solubility by altering the dielectric constant and hydrogen bonding capability of the vehicle, and by providing a hydrophobic microenvironment. Commonly used cosolvents include ethanol, polyethylene glycol, and propylene glycol. In addition, cyclic polysaccharides, such as cyclodextrins, that have a hydrophobic cavity and a hydrophilic exterior are often used for drug solubilization. Complexation soluble intermolecular complex. easily reversible complex formation in biological fluids E.g. iodine with a 10-15% solution of polyvinylpyrrolidone C h e m i c a l m o d I f I c a t I on As a last resort Chemical modification of a drug may be necessary to produce a water-soluble derivative. Examples; sodium phosphate salts of hydrocortisone, prednisolone and betamethasone. poorly soluble acids and bases being converted to a salt form to increase water solubility chloramphenicol sodium succinate is inactive antimicrobial agent but is soluble in aqueous solvent Particle size control The size and shape of very small particles, if less than 1 µm diameter, can affect their solubilities. As particle size decreases solubility will increase. Control of the pH of the solution A quantitative application of the Henderson-Hasselbalch equation will enable the solubility of such a drug in water at a given pH to be determined, provided its pKa and the solubility of its unionized species are known The solubility of a weak base can be increased by lowering the pH of its solution The solubility of a weak acid is improved by an increase in pH This can be achieved by the use of buffers Non-aqueous solutions Fixed oils of vegetable origin Alcohols Polyhydric alcohols Dimethylsulphoxide Ethylether Liquid paraffin Miscellaneous solvents Non-aqueous solutions Non-aqueous solutions 1.Drug is unstable in aqueous solution 2. Drug is not completely dissolved at storage temperature 3. When slow release of medicine is required e.g. Depo therapy; IM testosterone and estradiol, oily solutions are used  Non-aqueous solutions Commonly used solvents include the following and are chosen with the following in mind; toxicity, irritancy and sensitizing potential Fixed oils of vegetable origin Olive oil, sesame oil, Almond oil (for Phenols), maize oil, cottonseed oil, soya oil and castor oil are all suitable for parenteral use, arachis oil, (for dimercaprol injection), for dissolving fat soluble vitamins e.g vitamins A and D. etc Alcohols Ethanol is the commonly used alcohol 15% ethanol exhibits antimicrobial activity, but because of its toxicity it is used orally or parenterally only at low concentrations, usually as a co-solvent with water. Polyhydric alcohols Only propylene glycol and glycerol are is used internally polyethylene glycols (PEG) widely used as co-solvents with alcohol or water for formulation of ointment bases mostly Non-aqueous solutions Dimethylsulphoxide used mainly as a solvent for veterinary drugs Ethyl ether widely used for the extraction of crude drugs used as a co-solvent with alcohol in some collodions. Liquid paraffin Other formulation additives Buffers Density modifiers Isotonicity modifiers Viscosity enhancement Preservatives Reducing agents and antioxidants Sweetening agents Flavours and perfumes Colours Other formulation additives Buffers when dissolved in a solvent, will enable the solution to resist any change in pH should an acid or an alkali be added. Most pharmaceutically acceptable buffering systems are based on carbonates, citrates, gluconates, lactates, phosphates or tartrates. Borates can be used for external application, but not to mucous membranes or to abraded skin. Density modifiers For formulating spinal anaesthetics. The most widely used material for density modification is dextrose Isotonicity modifiers dextrose and sodium chloride. Used in Solutions for injection, solutions for application to mucous membranes, large-volume solutions for ophthalmic use; to be made iso-osmotic with tissue fluid to avoid pain and irritation Viscosity enhancement For topical solutions Examples include; povidone, hydroxyethylcellulose and carbomer Other formulation additives Preservatives Care should be taken that adsorption of the preservative onto the container from the product does not occur, and its efficiency is not impaired by the pH of the solution or by interactions with other ingredients. e.g. Parahydroxybenzoic acid esters interact with non ionic surfactants like sorbitan esters Reducing agents and antioxidants - to control the decomposition of drugs e.g. sodium metabisulphite (reducing agent) and the antioxidants; butylated hydroxyanisole and butylated hydroxytoluene. Sweetening agents sucrose, are traditionally the most widely used sweetening agents. sorbitol, mannitol and, to a lesser extent glycerol are also used artificial sweeteners (intense sweeteners)– are also used (at concentrations of less than 0.2%) Examples are; aspartame (E951), which is a compound of L-aspartic acid and L-phenylalanine, acesulfame potassium (E950), thaumatin (E957), sodium cyclamate (E952), neohesperidine DC (E959) and saccharin Advantages; use in diabetics, reduced dental carries disadvantages; after taste, hence used with sugars sometimes Other formulation additives Flavours and perfumes For highly unpleasant drugs and to improve patient compliance especially in paediatrics Other formulation additives Colours Reason for including colours in medicine to improve the attractiveness of the product. to enable easy product identification Particularly of poisonous materials, including weed killers and mineralized methylated spirit, and, for example, to differentiate between the many types of antiseptic solution used in hospitals for the disinfection of skin, instruments, syringes Ensure that any colour chosen is acceptable in the country in which the product is to be sold. A colour that is acceptable in one country may not be acceptable in Another Example of colourants: water-soluble dye amaranth - also known as Bordeaux S, Cl Food Red 9, Cl Acid Red 27, Colour Index Number 16185 Other formulation additives Colours A range of both natural and synthetic colours E.g. Natural dyes; carotenoids, chlorophyll, anthocyanins, and miscellaneous group which includes riboflavines, caramel and extracts of beetroot variations in availability and chemical composition may cause formulation difficulties. Synthetic or (coal tar) dyes; sodium salts of sulphonic acids Care must also be taken to ensure that any dye used is not adversely affected by pH or by ultraviolet radiation, or by the inclusion of oxidizing or reducing agents or surfactants.  The International Pharmacopoeia - Ninth Edition, 2019 Liquid preparations for oral use 2024/10/13 55 65 Liquid preparations for oral use Manufacture The manufacturing process for liquid preparations for oral use should meet the requirements of Good Manufacturing Practice (G MP). The following information is intended to provide broad guidelines concerning the critical steps to be followed during product ion of liquid preparations for oral use. In the manufacture of liquid preparations for oral use, measures are taken to: ensure that all ingredients are of appropriate quality minimize the risk of microbial contamination (see recommendations in chapter MICROBIOLOGICAL QUALITY OF NON-STERILE PRODUCT S: RECOMMENDED ACCEPTANCE CRITERIA FOR PHARMACEUTICAL PREPARATIONS of the supplementary information section.); minimize the risk of cross-contamination During the development of a preparation, the formulation for which contains one or more antimicrobial preservatives, the effe ctiveness of the chosen preservative system shall be demonstrated to the satisfaction of the relevant regulatory authority. Appropriate measures should also be taken to optimize the stability of the active ingredient(s) in liquid formulations includ ing those prepared from powder or granules. Additional measures should be taken so that, when stored under the conditions stated on the label, oral s olutions are not subject to precipitation and oral suspensions are not subject to fast sedimentation, lump formation or caking. During development of a single-dose liquid preparation for oral use it shall be demonstrated that the nominal content can be wit hdrawn from the container. In the production of liquid preparations for oral use containing dispersed particles, measures are taken to ensure a suitable and controlled particle size and, where appropriate, crystal structure (polymorphic and/or solvated forms) with regard to the intended use. Throughout manufacturing, certain procedures should be validated and monitored by carrying out appropriate in -process controls. Liquid preparations for oral use Page 1 of 4 The International Pharmacopoeia - Ninth Edition, 2019 Liquid preparations for oral use. These should be designed to guarantee the effectiveness of each stage of production. In-process controls during the manufacture of oral liquids should include pH and fill volume. The validation of the manufacturing process and the in -process controls are documented. 2024/10/13 55 66 Uniformity of mass Liquid preparations for oral use that are presented as single-dose preparations comply with the following test. Weigh individually the contents of 20 containers, emptied as completely as possible, and determine the average mass. Not more than 2 of the individual masses deviate by more than 10% from the average mass and none deviates by more than 20%. Uniformity of mass of doses delivered by the measuring device The measuring device provided with a multidose liquid preparation for oral use complies with the following test. Weigh individually 20 doses taken at random from one or more multidose containers with the measuring device provided and determine the individual and average masses. Not more than two of the individual masses deviate by more than 10% from the average mass and none deviates by more than 20%. Containers The containers should be made of material that will not adversely affect the quality of the preparation by, for example, leaching or sorption. Liquid preparations for oral use that contain light- sensitive active ingredients are supplied in containers that are lightresistant. Except where indicated in the individual monograph, containers should be made from material that is sufficiently transparent to permit the visual inspection of the contents. If the preparation contains volatile ingredients, the liquid preparation for oral use should be kept in a tightly closed container. 2024/10/13 55 67 Labelling:. Every pharmaceutical preparation must comply with the labelling requirements established under Good Manufacturing Practice The label should include: (1) the name of the pharmaceutical product; (2) the name(s) of the active ingredients; INNs should be used wherever possible; (3) the amount of active ingredient in a suitable dose-volume; (4) the name and concentration of any antimicrobial preservative and the name of any other excipient; (5) the batch (lot) number assigned by the manufacturer; (6) the expiry date and, when required, the date of manufacture; (7) any special storage conditions or handling precautions that may be necessary; (8) directions for use, warnings, and precautions that may be necessary; (9) the name and address of the manufacturer or the person responsible for placing the product on the market 2024/10/13 55 68 Labelling cont. If the Liquid preparation for oral use is supplied as granules or powder to be constituted just before issue for use, the label should include: (1) that the contents of the container are granules or powder for the preparation of an oral liquid; (2) the strength as the amount of the active ingredient in a suitable dose-volume of the constituted 2024/10/13 55 69 Requirements for specific types of liquid preparations for oral use Oral solutions Definition Oral solutions are clear Liquid preparations for oral use containing one or more active ingredients dissolved in a suitable vehicle. Visual inspection Inspect the solution. It should be clear and free from any precipitate. A change in colour or cloudiness of solutions may indicate chemical degradation or microbial contamination. 2024/10/13 55 70 Requirements for specific types of liquid preparations for oral use Oral drops Definition Oral drops are Liquid preparations for oral use that are intended to be administered in small volumes with the aid of a suitable measuring device. They may be solutions, suspensions or emulsions 2024/10/13 55 71 Requirements for specific types of liquid preparations for oral use Visual inspection Inspect the drops. Drops that are solutions should be clear and free from any precipitate. Evidence of physical instability of drops that are suspensions is demonstrated by the formation of flocculants or sediments that do not readily disperse on gentle shaking. Evidence of physical instability of drops that are emulsions is demonstrated by phase separation that is not readily reversed on gentle shaking. A change in colour (or cloudiness of solutions) may indicate chemical degradation or microbial contamination of the drops. Dose and uniformity of dose of oral drops Into a suitable, graduated cylinder, introduce by means of the dropping device the number of drops usually prescribed for one dose or introduce by means of the measuring device the usually prescribed quantity. The dropping speed does not exceed 2 drops per second. Weigh the liquid, repeat the addition, weigh again and carry on repeating the addition and weighing until a total of 10 masses are obtained. No single mass deviates by more than 10% from the average mass. The total of 10 masses does not differ by more than 15% from the nominal mass of 10 doses. If appropriate, measure the total volume of 10 doses. The volume does not differ by more than 15% from the nominal volume of 10 doses. Containers Oral drops are normally supplied in suitable multidose containers that allow successive drops of the preparation to be administered. 2024/10/13 55 72 Powders for oral solutions, oral suspensions or oral drops Presentations of powder (usually single-dose presentations, for example, a small sachet) that are intended to be issued to the patient as a powder, to be taken in or with water or another suitable liquid, are outside the scope of this general monograph. Such preparations are controlled by the monograph for Oral powders. Definition Powders for oral solutions, suspensions or drops are multidose preparations consisting of solid, loose, dry particles of varying degrees of fineness. They contain one or more active ingredients, with or without excipients and, if necessary, authorized colouring matter and flavouring substances. They may contain antimicrobial preservatives and other excipients in particular to facilitate dispersion or dissolution and to prevent caking. After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral solutions, Oral suspensions or Oral drops, as appropriate. 2024/10/13 55 73 Powders for oral solutions, oral suspensions or oral drops Manufacture In the manufacture of powders for oral solutions, suspensions or drops, the components of the powder mixture are passed through a sieve to remove lumps and particle aggregates. The weighed masses of the sieved components, preferably of a narrow particle size distribution, are then transferred to a suitable mixer. The greatest risk of segregation of the powder mixture usually occurs when emptying the mixer container and when the powder mixture is dosed into the containers. Ensuring the suitability of the mixing equipment and the dosing devices is, therefore, critical. Visual inspection Inspect the powder. Evidence of physical instability is demonstrated by noticeable changes in physical appearance, including texture (for example, clumping). A change in colour may indicate chemical degradation or microbial contamination. 2024/10/13 55 74 Granules for oral solutions or suspensions Presentations of granules that are intended to be issued to the patient as granules to be swallowed as such, to be chewed, or to be taken in or with water or another suitable liquid, are outside the scope of this general monograph. Definition Granules for oral solutions or suspensions are multidose preparations consisting of solid, dry aggregates of powder particles sufficiently resistant to withstand handling. They contain one or more active ingredients with or without excipients and, if necessary, authorized colouring matter and flavouring substances. They may contain antimicrobial preservatives and other excipients in particular to facilitate dispersion or dissolution and to prevent caking. After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral solutions or Oral suspen sions, as appropriate. Visual inspection Inspect the granules. Evidence of physical instability is demonstrated by noticeable changes in physical appearance, including texture (for example, clumping of granules, presence of loose powder). A change in colour may indicate chemical degradation or microbial contamination. 2024/10/13 55 75 Safety concerns An important aspect of Good Manufacturing Practice for all pharmaceutical products is assuring the quality of all the starting materials used. The need for analytical testing to check the identity and quality of starting materials is explained in detail in section 14 of the current WHO GMP guidelines1. Failure to ensure that starting materials are of the required quality can have very serious consequences. Increasingly countries are dependent on the importation of starting materials for use in the production of medicines. Starting materials often change hands many times before reaching the manufacturer of the final marketed product and there are many opportunities for the material to undergo relabelling along the distribution and trade chain (see WHO Guideline on Good Trade and Distribution Practices for Pharmaceutical Starting Materials1). As a result, starting materials required for production of pharmaceutical products can become contaminated or materials may be supplied that no longer correspond to what is stated on the label in terms of quality or identity, either accidentally or as a result of negligence and sometimes fraud. The most documented incidents of contamination involve liquid preparations for oral use manufactured with excipients such as glycerol and propylene glycol that have been contaminated, adulterated or mixed up with diethylene glycol. Such incidents have been responsible for hundreds of deaths throughout the world (see, fofor example, editorial in WHO Bulletin 2001, 79(2)). Ingestion of diethylene glycol often leads to death through kidney failure. 1 For the current edition of WHO guidelines, please consult the WHO Medicines web site: http://www.who.int/medicines/en/. 2024/10/13 55 76 FORMULATION COMPONENTS AND MANUFACTURING PROCESS 2024/10/13 55 77  FORMULATION COMPONENTS AND MANUFACTURING PROCESS Typical formulation components of oral solution dosage forms include API Vehicle, which is usually aqueous but could also be vegetable oil Buffer for maintaining desired solution pH Sweetener, flavor, and color for improving palatability Taste masking agent, if required Antimicrobial preservative(s) Antioxidant(s), if and when needed Cosolvent(s) and/or surfactant(s), if and when needed Solubiliser, if and when needed 2024/10/13 55 78  MANUFACTURING PROCESS Typical manufacturing process for solution dosage forms involves simple mixing of all ingredients to make a solution. However, several process variables need to be carefully controlled to ensure a reproducible and high-quality manufacturing process, such as; ✓sequence of addition of ingredients, ✓process equipment and ✓parameters to control foaming and mixing dynamics, and ✓temperature control. Additive considerations include pH adjusters, flavors, sweeteners, colorants, preservatives, viscosity enhancers , and so forth 2024/10/13 55 79 MANUFACTURING PROCESS Vehicles used in oral solutions primarily include water, ethanol, glycerine, syrups, and various blends of these ingredients. Although oral solutions are usually ready to administer, they sometimes have to be diluted or prepared before administering to the patient. This preparation is utilized for drugs that are not very stable in solution. Such dosage forms are marketed as powder for oral solution and are required to be dissolved in water by the patient, pharmacist, or nurse immediately prior to administration. 2024/10/13 55 80  Large-scale pharmaceutical mixing vessels. (Courtesy of Schering Laboratories.) 2024/10/13 55 81 Preparation of Solutions Solutions are prepared by adding solute in to solution Solution may be aided by several means e.g; Heat Agitation (mostly vigorous) Reduction of the particle size of the solute Use of solubilising agents 2024/10/13 55 82 Heat Most chemical agents are more soluble at elevated temperatures than at room temperature or below because an endothermic reaction between the solute and the solvent uses the energy of the heat to enhance dissolution. An increase in the rate of solution rather is achieved by heat rather than an increase in solubility 2024/10/13 55 83 Heat Care should be taken when using heat to aid solubility because Too much heat may destroy the API or other excipients Care must be taken to not subject the pharmaceutical material to excessive heat because for many medicinal agents are destroyed at elevated temperatures and the advantage of rapid solution may be completely offset by drug deterioration Volatile solutes or solvents may be lost to the atmosphere Some chemicals may dissolve exothermically certain chemical agents, particularly calcium salts, undergo exothermic reactions as they dissolve and give off heat. For these agents heating will discourage solution 2024/10/13 55 84 Reduction of the particle size of the solute In addition to or instead of raising the temperature of the solvent to increase the rate of solution, a pharmacist may choose to decrease the particle size of the solute by comminution (grinding a solid to a fine state of subdivision) with a mortar and pestle on a small scale) or by an industrial micronizer on a larger scale. 2024/10/13 55 85  Pharmaceutical Micronizer Jet Mill 2024/10/13 55 86  Pharmaceutical Mill Micronisers 2024/10/13 55 87 Mixing Most solutions are prepared by simple mixing of the solutes with the solvent. On an industrial scale, solutions are prepared in large mixing vessels with ports for mechanical stirrers (as bellow) When heat is desired, thermostatically controlled mixing tanks may be used 2024/10/13 55 88  Large-scale pharmaceutical mixing vessels. (Courtesy of Schering Laboratories.) 2024/10/13 55 89 Mixing Mixing is a unit operation in industrial pharmacy (together with, milling and drying and clarification etc). Definition Mixing is the process of thoroughly combining different materials to produce a homogenous product Compared with Blending Blending is the process of combining materials and relatively gentle process compared to mixing 2024/10/13 55 90 Mixing Mechanisms Four categories of process are involved in the mixing mechanism Bulk transport Turbulent Mixing Laminar Mixing Molecular diffusion 2024/10/13 55 91  Mixing Equipment Impellers (Propellers, Turbines, Paddles) Axial Flow impeller Radial Flow impeller Tangential flow impellers Air jets Fluid Jets Baffles (Refer to the attached document and Chapter 1; Industrial Pharmacy Lieberman 2024/10/13 and Lachman 55 92 Impellers Impellers impellers are the part of the mixer that does the actual mixing: as they rotate they create fluid flow. These flow patterns are the primary considerations when designing a mixer because creating the right flow pattern is critical to achieving the desired result. Impellers The most common flow patterns in mixing are axial (down and up) and radial (side to side) flow. Axial Flow Impellers Axial (down and up) pumping is an important flow pattern because it addresses two of the most common challenges in mixing; solid suspension and stratification. Axial Turbine Impeller  Radial Flow Impellers Radial Flow Impellers Unlike axial impellers, radial impellers are commonly selected for low level mixing (known as a tickler blade) or elongated tanks. They typically give high shear rates because of their angle of attack. They also have a relatively low pumping number, making them the most sensitive to viscosity. Radial impellers do not have a high tank turnover flow like axial flow impellers Radial Turbine Impeller Impellers https://proquipinc.com/industrial-mixing-basics-types-of-mixing- impellers/ https://www.dynamixinc.com/mixing-101-the-basic-principles-of- mixing-and-impeller  Clarification of solutions Chapter 21; Aulton 2nd editon 2024/10/13 55 101  Packaging and Storage of Pharmaceutical Solutions 2024/10/13 55 102 Types of packaging materials A. Glass o Glass has been widely used as a drug packaging material. o Glass is composed of sand, soda ash, limestone, and cullet. o Si, Al, Na, K, Ca, Mg, Zn & Ba are generally used into preparation of glass Advantages o They are hygienic and suitable for sterilization o They are relatively non-reactive ( depending on the grade chosen) o It can accept a variety of closures o They can be used on high speed packaging lines o They are transparent. o They have good protection power. o They can be easily labeled. Disadvantages o It is relatively heavy o Glass is fragile so easily broken. o Release alkali to aqueous preparation 2024/10/13 55 103 QUALITY ATTRIBUTES Important quality attributes of a solution dosage form include; ❑ physical stability ❑Chemical stability ❑biological stability ❑palatability ❑deliverability of the dose and ❑dosage uniformity. 2024/10/13 55 104 QUALITY ATTRIBUTES Physical stability refers to the lack of precipitation, change in color, or any other change in physical appearance or perception of the dosage form. Chemical stability refers to the lack of unacceptable chemical degradation of the drug during the shelf life of the product under recommended packaging and storage conditions. The drug product must meet the predetermined requirements of minimum potency of the active pharmaceutical ingredient (API) maximum levels of known and unknown impurities. Biological Stability - since most of the solutions are formulated in aqueous vehicle, special measures must be taken that they remain free of any microbial growth. 2024/10/13 55 105 QUALITY ATTRIBUTES Palatability of the dosage form is usually enhanced by the use of sweeteners, flavors, and colorants. For especially bitter or otherwise unpleasant tasting drugs, taste masking approaches such as drug adsorption on an ion exchange resin may be utilized. Deliverability of the dose refers to the ability to retrieve the labeled amount of liquid from the dispensed bottle under normal usage conditions. 2024/10/13 55 106 QUALITY ATTRIBUTES The uniformity of content of API in each dispensed unit dose should be demonstrated for inter-dose variability within the doses dispensed from a given multi-dose container (bottle) and also for bottle-to- bottle uniformity in the concentration of the API. Viscosity of the formulation is an important determinant of its deliverability and uniformity of content. 2024/10/13 55 107 Types of preparations Liquids for cutaneous application 319 Lotions, liniments, paints and collodions 319 Ear preparations 320 Eye preparations 320 Irrigations 320 Mouthwashes and gargles 320 Nasal products 320 2024/10/13 55 108 Types of preparations Oral liquids Elixirs Linctuses Mixtures and draughts Parenteral products Rectal preparations Intermediate products Aromatic waters and spirits Extracts, infusions and tinctures Syrups 2024/10/13 55 109  Other Oral Liquid dosage forms – Single phase Oral Liquid dosage forms – Single phase Elixirs An elixir is a solution of a potent or nauseous drug. If the active agent is sensitive to moisture, it may be formulated as a flavoured powder or granulation and then simply dissolved in water immediately prior to administration. The dosage is usually taken using a 5 mL medicine spoon, although smaller volumes can be given using a volumetric dropper. Elixir: Definition Elixir are clear, sweetened hydro-alcoholic solution. These are Intended for oral use and are usually flavoured to enhance palatability. Usually less sweet than syrups and less viscous. 2024/10/13 55 112 Classification of Elixirs They are classified into two classes, a. Non medicated elixirs – vehicles, b. Medicated elixir – used for therapeutic effects 2024/10/13 55 113 2024/10/13 55 114 Linctuses A linctus is a viscous preparation, usually prescribed for the relief of cough. It normally consists of a simple solution of the active agent in a high concentration of sucrose, often with other sweetening agents. Administered in multiples of 5 mL, should be sipped slowly and not be diluted beforehand. The syrup content has a demulcent action on the mucous membranes of the throat. For diabetic use the sucrose is usually replaced by sorbitol and/or synthetic sweeteners. Mixtures Mixtures are usually aqueous preparations that can be in the form of either a solution or a suspension. Most preparations of this type are manufactured on a small scale as required, and are allocated a shelf-life of a few weeks before dispensing. Doses are usually given in multiples of 5 mL using a metric medicine spoon. Draughts A draught is a mixture of which only one or two large doses of about 50 mL are given, although smaller doses are often necessary for children Intermediate products Products designed for use during the manufacture of other preparations and which are rarely administered themselves. Aromatic waters Aqueous solutions of volatile materials used mainly for their flavouring properties. E.g. peppermint water, anise water (carminative), chloroform water (preservatives They are usually manufactured as concentrated waters and are then diluted, traditionally 1:40 in the final preparation. Aromatic spirits alcoholic solutions of volatile materials, mainly used as flavouring agents Infusions, extracts and tinctures Infusions, extracts and tinctures are terms used for concentrated solutions of active principles from animal or vegetable sources. Infusions are prepared by extracting the drug using 25% alcohol, but without the application of heat. Traditionally these preparations are then diluted 1:10 in the final product. Extracts are similar products that are then concentrated by evaporation. Tinctures are alcoholic extracts of drugs but are relatively weak compared with extracts. Syrups Syrups are concentrated aqueous preparations of a sugar or sugar substitute with or without flavouring agents and medicinal substances. Types of syrup: a. Medicated syrups: Syrups containing flavouring agents with medicinal substances. b. Flavoured Syrups: Used as vehicles for unpleasant tasting medications; the result is medicated syrup. 2024/10/13 55 120 Syrups (cont.) medicated sugar solutions (sucrose, unless made of artificial sweetener) can contain up to 85% of sugars, they are capable of resisting bacterial growth by virtue of their osmotic effect. lower concentrations will also contain sorbitol, glycerol or propylene glycol in order to maintain a high osmotic gradient. because of surface dilution often contain additional preservatives. crystallization of the sugar problem solve by use of invert sugar (mixture of glucose and fructose) Advantages of Syrups: a. Ability to disguise bad taste of medication. b. Thick character of syrup has soothing effect on irritated tissues of throat. c. Contain little or no alcohol. d. Easy to adjust the dose for a child’s weight 2024/10/13 55 122