Pharmaceutics 1 Lecture 2 (Solutions) PDF

Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) Pharmaceutical solutions Excipients of Pharmaceutical Solutions  Solvents/Co-solvents The first choice of solvent is water; however, when another solvent (co-solvent) shou...

Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) Pharmaceutical solutions Excipients of Pharmaceutical Solutions  Solvents/Co-solvents The first choice of solvent is water; however, when another solvent (co-solvent) should be used its choice of depends on: a) its ability to dissolve the ingredients of formulation b) its compatibility with the drug and excipients c) the route of administration The common pharmaceutical so-solvents include:- Ethanol Glycerol Propylene glycol Isopropanol Polyethylene Glycol (PEG-200/400)  Ethanol and propylene glycol are the most used co-solvents and both of them are non-toxic for the parenteral formulations.  When using ethanol as co-solvent for solutions of internal use (orally or parenterally), its amount used should be limited.  Sweetening Agents (Sweeteners) Due to the strong unpleasant taste of drugs in liquids, sweeteners are essential components of oral liquid dosage forms. Sweeteners are classified into:- 1) Nutritive (caloric) that contain calories 2) Non-nutritive (non-caloric) which are recommended for diabetic patients  In general, the most commonly used sweeteners include:- - Caloric: Sucrose Sorbitol Mannitol Liquid Glucose Honey Molasses 1 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) - Non-caloric: Saccharin Aspartame Sucralose Acesulphame-K Properties of Common Sweeteners  Sucrose is the most widely used sweetener and it inhibits the growth of microorganisms in solution at concentrations of 65 - 85 wt%.  Sorbitol and glycerin are usually used with sucrose to reduce its crystallization.  Liquid glucose is extremely viscous solution of glucose that imparts both the syrupy consistency and sweetness for oral liquid dosage forms.  Saccharin is a non-nutritive synthetic sweetener and it has approximately 500 times the sweetening power of sucrose. In order to increase sweetening power of saccharin, it is commonly used as a sodium salt, due to the higher aqueous solubility of sodium saccharin.  Saccharin is the first alternative of sucrose for diabetics and obeses.  Sucralose is a non-nutritive sweetener that has sweetening power approximately 600 times higher than sucrose.  Sucralose differs from sucrose by substitution of three chlorines (-Cl) for hydroxyl groups (-OH); consequently, this substitution makes sucralose a heat-stable and wide pH-stable. 2 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2)  Flavoring Agents (flavorings) The flavoring agents are aromatic and volatile materials and they are essential components in oral liquid dosage forms to aid in masking the disagreeable taste of drugs. The flavorings used in oral pharmaceutical solutions may be natural and synthetic. - Examples of natural flavorings: Vanillin, Anise oil, Ginger oil, Peppermint oil, Menthol, Orange oil and Lemon oil. - Examples of synthetic flavorings: Raspberry (3,5-Dimethyl-1,2-Cyclopentadione), Strawberry (Ethyl Methylphenylglycidate), Caramel (3,5-Dimethyl-1,2-Cyclopentadione), Apple (Ethyl 2-methylpentanoate) and Banana (Isopentyl Acetate).  The flavorings should be selected according to:- a) The age group of patients For example: fruit and strawberry flavors are preferable for children, whilst mint flavor (Peppermint) is not. b) The taste of drug For example: citrus flavors are often used to mask acid-tasting drugs (sour taste). c) The solubility of flavor in the vehicle 3 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2)  Coloring Agents (colorants) The colorant should be selected from the FD&C-certified colorants and it should be used at the lowest possible concentration to produce the desired color (0.001%). According to solubility, colouring agents are classified as: a) Dye: Colouring agents which are soluble in water are called dye and they are often organic compounds. For example, Safranin, FD&C red #4, FD&C yellow #5. b) Pigment: Colouring agents which are insoluble in water are called pigment. For example, Red Ferric Oxide, Titanium Oxide, Lead Oxide, Indigo, and β-Carotene. Uses of Colouring Agents 1) Colouring agents are used mainly to impart a characteristic appearance to a pharmaceutical dosage form. 4 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) 2) To identify and differentiate drug products during manufacturing, packaging, distribution, and using by patients. 3) The use of different colouring agents for different strengths of the same drug. 4) Coloring agents are to prevent counterfeiting. 5) To improve patient acceptance. 6) To protect photolabile API of the dosage form.  The colorants are basically highly chemically reactive compounds; thus, their shade (color intensity) and stability are affected by:- 1) The pH of pharmaceutical solution 2) The microbiological activity within the pH of pharmaceutical solution 3) Exposure to light 4) The compatibility of colorant with other ingredients (drug and excipients). 5 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) Take in your mind: color is usually chosen according to the flavor of the product, for example, greenish yellow for lemon or red for cherry, and so on.  Buffers (Buffering Agents) Buffers are conjugate acid-base systems of a weak acid with its salt (base conjugate) or a weak base with its salt (acid conjugate), and they are used to stabilize the pH of solutions.  The pharmacist should consider the use of co-solvents could potentially precipitate buffers. Since they are conjugate acid-base systems, the co-solvents could shift the pKa of the buffer or salt. The suitable buffer system should have high buffer capacity to maintain the pH of solutions during storage, where the adequate capacity of a buffer system will be within 1 pH unit of change.  The buffer capacity is maximum when pH = pKa The commonly used buffers are acetates, citrates, phosphates, and glutamates. Table below shows their pKa and the pH range of their good capacity.  Preservatives In general, the aqueous liquid preparations must contain a preservative, becuase they are suitable media for bacterial growth and highly susceptible to the bacterial contamination for many reasons:- 6 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) 1) They are usually multi-dosing products that increase the risk of contamination. 2) They usually contain sugars which are nutritive substances for the microorganisms, leading to microbial growth. 3) The non-sterile conditions of manufacturing of many liquid products may contribute to microbial contamination. 4) The risks associated with DW and the used raw materials of natural origin that may contain viable spores. Therefore, it is essential to add a preservative to protect the pharmaceutical solutions against the microbial spoilage.  The major concern with using preservatives is their toxicity, particularly for children and elderly patients. Therefore, the preservative used must be:- 1) Safe and lack of toxicity 2) Physically and chemically stable 3) Soluble in the used solvent or cosolvent 4) Effective against a broad spectrum of microorganisms 5) Compatible with drug and excipients Types of Preservatives There are mainly four major types of preservatives: 1) Acidic 2) Neutral 3) Mercurial 4) Quaternary Ammonium Compounds  The acidic preservatives are the most widely used for oral preparations, which are classified to two groups:- a) Esters of -Hydroxybenzoic acid, such as methyl paraben, ethyl paraben, propyl paraben and butyl paraben. These preservatives are called Parabens. 7 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) These preservatives are sufficiently soluble in aqueous systems and possess both antifungal and antibacterial properties. b) Salts of benzoic acid, such as sodium benzoate, potassium benzoate. They are in salt forms to increase their solubility and so efficacy.  The three other types of preservatives are usually used for ophthalmic, nasal, and parenteral products. However, the mercurials and quaternary ammonium compounds have major incompatibilities, where: 1. Mercurials (e.g. Thiomerosal) are readily reduced to give the free mercury by reducing agents (Antioxidants). 2. Quaternary ammonium compounds (Benzalkonium chloride or Benzethonium chloride) are inactivated by anionic substances (such as anionic surfactants) because they are positively charged. 8 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) Finally, in practice a combination of two or three of preservatives is commonly used to achieve the desired efficacy with lower toxicity and wide broad spectrum.  Antioxidants Some active pharmaceutical ingredients (APIs) can be chemically degraded through their oxidation. Oxidation reactions are mainly mediated by free radicals or molecular oxygen, and are often catalyzed by metal cations.  Therefore, antioxidants are usually added in combination with chelating agents such as edetic acid derivatives (Ethylene diamine tetraacetic acid EDTA) or citric acid. The chelating agents form complexes with metal cations which prevent them from catalyzing the oxidation of drug. 9 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) The Common Antioxidants 1) Sulfites are the most common antioxidants used in aqueous pharmaceutical solutions, where:  sodium metabisulfite (Na2S2O5) is used at low pH  sodium bisulfite (NaHSO3) is used at near neutral pH  sodium sulfite (Na2SO3) is used at basic pH 2) Ascorbic acid (Vit C) which is usually used with citric acid that acts as chelating agent and increases the antioxidative effect of ascorbic acid. 10 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) 3) The hydrophobic antioxidants such as butylated hydroxytoluene (BHT) and butylated hydroxylanisole (BHA) which are used for oily pharmaceutical solutions.  Viscosity-Increasing Agents The consistency of pharmaceutical solutions can be increased in order to:-  Improve the pourability of oral solutions.  Improve the residence time of ophthalmic or nasal solutions. The consistency of pharmaceutical solutions can be increased by adding viscosity-increasing agents such as:-  Derivatives of Polyvinylpyrrolidone (PVP): Povidone, Crospovidone.  Derivatives of polyacrylic acid (Carbomers): Carbopol 934, Carbopol 940, Carbopol 947.  Polysaccharides: Cellulose derivatives, Tragacanth, Acacia (Gum Arabic), Agar. 11 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (2) However, the highly viscous systems could resist the dilution of oral solution by the gastrointestinal fluids which may delay the drug release and absorption. 12