Pharmaceutics I Lecture 2: Pharmaceutical Solutions (Cont.) PDF

Alexandria university Faculty of Pharmacy Department of Pharmaceutics PharmD Program Semester Three Pharmaceutics I (02-06-01202) PHARMACEUTICS I Lecture 2: PHARMACEUTICAL SOLUTIONS (Cont.) Dr. Shaimaa Osama, PhD...

Alexandria university Faculty of Pharmacy Department of Pharmaceutics PharmD Program Semester Three Pharmaceutics I (02-06-01202) PHARMACEUTICS I Lecture 2: PHARMACEUTICAL SOLUTIONS (Cont.) Dr. Shaimaa Osama, PhD 1 Intended learning outcomes After completion of this lecture, you will be able to: Describe the process of solutions preparation Differentiate between different methods used for enhancement of drug solubility. Describe stability aspects of solutions and how different factors increase or decrease solutions stability and possible incompatibilities. Define the various types of oral and topical liquid dosage forms. 2 THE PROCESS OF SOLUTIONS PREPARATION 3 PREPARATION OF SOLUTIONS: TECHNIQUES Dissolution The active ingredient is dissolved in the appropriate solvent(s) to form a homogeneous solution. Mixing The solution is thoroughly mixed to ensure uniform distribution of the drug and other excipients. Filtration The solution may be filtered to remove any undissolved particles or impurities, ensuring clarity and stability. Packaging The solution is carefully packaged in appropriate containers, such as glass or plastic bottles, to protect it from environmental factors and ensure long-term stability.  ENHANCEMENT OF DRUG SOLUBILITY Almost all pharmaceutical solutions are unsaturated with solute. Drug solubility in water depends on a number of factors such as the drug’s molecular structure, crystal structure, particle size, pka and the pH of the medium ( the drug is a weak acid/base or a salt). The nature of the solubility enhancer depends on the drug molecule and the route of administration, as well as the intended patient population. Different approaches to enhancing drug solubility in solutions are described. pH Micelles & Co solvents Cyclodextrins adjustment Surfactants 5  PH ADJUSTMENT Most existing drugs are either weak acids or weak bases. In solution, an equilibrium exists between the undissociated drug molecules and their ions. Since ions are more soluble in water than neutral molecules, changing the pH of the medium to increase ionization of the drug is a common technique for increasing drug solubility in an aqueous medium. Weakly acidic drugs are ionized when the pH of the solvent is increased. Conversely, lowering pH favours ionization of weakly basic drugs. pH can be adjusted using acids or alkali, or using buffers such as citrate, acetate, phosphate and carbonate buffers. Extremes of pH should be avoided so that the solution is physiologically acceptable. 6  PH ADJUSTMENT The chosen pH should not adversely affect the stability of the drug and excipients. PH can also be important for the optimal functioning of excipients. For example, the ionization, and subsequently the activity of a preservative may be influenced by the pH of the medium. Bioavailability of the drug should also not be compromised by a change in pH. Unionized drug molecules being absorbed to a greater extent through biological membranes than their ionized counterparts. The pH of a pharmaceutical solution is thus a compromise between drug solubility, stability and bioavailability, the function of excipients, and physiological acceptability of the product. 7  COMPLEXATION WITH CYCLODEXTRINS Cyclodextrins (CDs) are non-reducing cyclic glucose based oligosaccharides, comprising a variable number of d-glucose residues linked by α-(1,4) glycosidic linkages. The three most important CDs are alpha, beta and gamma cyclodextrins which consist of 6, 7 and 8 d- glucopyranosyl units, respectively, arranged in a ring. Three-dimensionally, CDs can be visualized as a hollow truncated cone. 8  COMPLEXATION WITH CYCLODEXTRINS The cavity in the cone has different diameters dependent on the number of glucose units in the ring; α-CD has a cavity diameter of about 0.55 nm, β-CD about 0.70 nm and γ-CD about 0.90 nm, with cavity volumes of 0.10, 0.14 and 0.20 ml/g, respectively. The interior cavity of cyclodextrins is hydrophobic, while their exterior is hydrophilic. 9  COMPLEXATION WITH CYCLODEXTRINS The –OH groups shown are actually attached to the top and bottom rims of the structure and not to either the inside or outside walls. The hydrophobic nature of the inside surface arises from the location of the –O– and C–H bonds of the glucose molecules being orientated there. The hydrophilic exterior results in CDs being soluble in water. The less polar interior can accommodate non-polar drug molecules via non- covalent interactions, thereby allowing the nonpolar drug to be ‘hidden’, enabling it to be molecularly dispersed in water. 10  COMPLEXATION WITH CYCLODEXTRINS Thus, drug inclusion within CDs effectively increases their aqueous solubility. Each cyclodextrin molecule can form complexes with one or more drug molecules. Upon administration, for example orally, of a solution containing a drug- CD complex, the drug can be released from the CD molecule and the free drug can then be absorbed through the gastrointestinal tract. 11  SURFACTANTS AND MICELLES Surfactants (surface-active agents) and amphiphiles are molecules which have two distinct regions in their chemical structure. One region is hydrophilic and the other hydrophobic. They reduce the surface tension of liquids, and self-assemble to form micelles once the critical micellar concentration (CMC) is reached. Poorly water-soluble drugs can be solubilized in micelles to enhance their aqueous solubility. 12  SURFACTANTS AND MICELLES The location of the solubilisate (the drug which is solubilized within the micelles) depends on its nature: Non-polar solubilisates being located within the micelles’ hydrophobic interior cores, Polar solubilisates are oriented with the polar group at the micellar surface. While slightly polar solubilisate partition between the Micelle surface and the core. The maximum amount of solubilisate which can be incorporated into a given system at a fixed concentration is known as the maximum additive concentration (MAC). 13  SURFACTANTS AND MICELLES The aqueous solubility of a wide range of drugs has been increased by surfactants. For example: Solubilization of steroids with polysorbates has allowed their formulation in aqueous ophthalmic preparations. While solubilization of the water-insoluble vitamins A, D, E and K has enabled the preparation of aqueous injections. 14  SURFACTANTS AND MICELLES The surfactant chosen for a particular drug must solubilize the drug and be compatible with it, and all the other components of the solution. The surfactant should not adversely influence the drug’s stability. The surfactant must also be non-toxic at the concentration used for the particular route of administration. The different means of enhancing drug solubility are often used in combination, as one approach is often insufficient to achieve the target drug concentration in a pharmaceutical solution. For example, pH adjustment and co-solvents are often used in combination. 15  SOLUTION STABILITY A pharmaceutical solution must be stable for the duration of its shelf - life (period of storage and use). It must retain the same physical, chemical, microbiological, therapeutic and toxicological properties that it possessed at the time of its manufacture. The product’s physical properties (e.g. Colour, clarity, viscosity, odour, taste) and efficacy must not change, and there should be no significant increase in toxicity. The drug’s chemical nature and potency must not change. The product should remain sterile or resistant to microbial growth. Stability Physical Chemical Microbiological Therapeutic Stability Stability Stability 16  PHYSICAL STABILITY Physical instability Effect on dosage form Sorption of drug to Drug loss container/closure Extraction of materials into liquid Potential toxicity/pH change from container/closure Shedding of particles from container Potential harm esp. with injection/poor appearance. Drug precipitation or degradation Loss of efficacy 17  CHEMICAL STABILITY There are several factors that might affect product stability such as temperature, light , humidity, and oxygen. In addition to solvent system composition, ionic strength, pH, excipient computability. Many drug molecules undergo chemical reactions, such as, hydrolysis, oxidation, decarboxylation, epimerization, polymerization, dehydration, with hydrolysis, oxidation and reduction being the most common. Chemical reactions occur more readily at high temperature, at certain pHs, in the presence of UV light and of substances which can act as a catalyst, and in solutions, where the drug is present as molecules. 18  CHEMICAL STABILITY The resulting loss of drug molecules can reduce the efficacy of the formulation and increase the drug’s toxicity if the products of the chemical changes are toxic. To reduce photo-oxidation, solutions are packaged in containers that do not allow light transmission. To reduce oxidation, antioxidants and/or metal chelators (as heavy metal ions catalyse oxidation) are used. Oxygen can be excluded, by purging the solution with nitrogen and creating a nitrogen headspace within the container. 19 INCOMPATIBILITIES Degradation of excipient due to interaction with other excipient or drug. Interaction of p-hydroxybenzoate preservative (parabens) with sorbitol forming transesterification product. 20 INCOMPATIBILITIES Degradation of the drug due to interaction with other drug or excipient. Sodium metabisulphite is commonly added to epinephrine (adrenaline) injection as an antioxidant. However, it reacts with the drug to form epinephrine sulphonate, and this is a significant degradation for epinephrine 21  MICROBIOLOGICAL STABILITY Deterioration due to the presence of microorganisms can either render the product harmful to the patient or have an adverse effect on the product’s properties. Microbiological deterioration is a critical factor in the stability of sterile products, once the container is opened. Injection products generally need to be used immediately the container is opened and products for use in the eye have a short in-use life once opened. To inhibit microbial growth during use in multidose products, preservatives are used. Use of single dose products e.g. injections and eye drops. The concentration of excipient must not decrease, which could happen, for example, the excipient degraded or adsorbed onto the container walls. 22 QUALITY CONTROL AND TESTING OF SOLUTION FORMULATIONS Parameter Importance Appearance Ensures the solution is clear, free of particulates, and meets visual specifications. pH Maintains the optimal pH range for drug stability and compatibility with the formulation. Assay Verifies the accurate concentration of the active ingredient in the solution. Sterility Confirms the absence of microbial contamination, especially for parenteral solutions. Stability Evaluates the chemical, physical, and microbial stability of the solution over its intended shelf life SOLUTION CLASSIFICATION ACCORDING TO ROUTE OF ADMINISTRATION Oral Oral cavity Topical Otic Nasal solution solution solution solution solution Pulmnary Rectal Vaginal Ocular Parenteral solution solution solution solution solution 24  ORAL SOLUTIONS Oral solutions are swallowed, in which case, the drug may exert a local effect on the gastrointestinal tract or be absorbed into the blood and exert a systemic action. Oral solutions are aqueous formulations. Solution pH is usually 7.0, although a range of pH 2–9 can be tolerated. Flavouring, colouring and sweetening agents are therefore added to enhance their appearance and taste. For convenience, the dose is usually in multiples of 5 ml, and the patient is given a 5 ml spoon with the solution. When smaller volumes are required, oral syringes are used. Solutions have a higher viscosity than water. Viscosity should be appropriate for palatability and pourability. 25  ORAL CAVITY SOLUTIONS Mouthwashes and gargles are used to treat local infection and inflammation in the oral cavity. Gingival solutions are applied to the gingivae. These are aqueous formulations and not intended to be swallowed and the drug exerts a local effect in the mouth. They must be palatable and acceptable to patients. Flavouring, colouring and sweetening agents are often added. As far as possible, the pH should be around neutral. 26  TOPICAL (SKIN/NAIL/HAIR) SOLUTIONS Solutions are applied to the skin for local and/or systemic effect and to the nail or hair for local effect. The vehicle may be aqueous or non-aqueous, and different types of formulations are available. A lotion is aqueous-based and is intended for application without friction. A liniment is an alcoholic or oily solution (or emulsion) designed to be rubbed into the skin. Paints and tinctures are concentrated aqueous or alcoholic antimicrobial solutions. A collodion is a solution of a polymer (pyroxylin), in a volatile organic solvent system (a mixture of ethanol and ether). Following application to the skin, the solvents evaporate, leaving a polymeric film on the skin. 27  TOPICAL (SKIN/NAIL/HAIR) SOLUTIONS Nail solutions are applied to the nail to treat nail diseases. Formulations which are easy to transfer from the container and will spread easily and smoothly are preferred. Formulation must adhere to site of application, without being difficult to remove. 28  OTIC SOLUTIONS Are instilled in the outer ear to exert a local effect. They are used to remove ear wax or to deliver anti-infective, anti-inflammatory and analgesic drugs. May be aqueous or non-aqueous solutions. Non-aqueous vehicles are predominantly used when ear wax removal is desired as ear wax can solubilize in them. As the residence time in the ear is higher for viscous solutions, the viscosity of aqueous solutions is increased by the use of polymers. Propylene glycol and glycerol solutions are naturally viscous and these enhance residence time. Solutions do not need to be isotonic as they are external preparations. 29 NASAL SOLUTIONS Nasal solutions, nose drops, nasal sprays, used for local, e.g Decongestant effect, or for systemic drug delivery. Nasal solutions are aqueous formulations. Solution pH is in the normal pH range of nasal fluids (pH 5.5 to 6.5). Solutions are usually isotonic to nasal fluids. Solution viscosity is similar to that of nasal mucus (which is higher than that of water). Flavouring or sweetening agents are sometimes used to mask taste, as a small proportion of nasal solution may be swallowed following nasal administration. Multidose solutions require preservatives. 30 PULMONARY (INHALED) SOLUTIONS Pulmonary inhaled solutions are administered by pressurized metered-dose inhalers or by nebulizers for local or systemic effect. Solutions used in nebulizers are aqueous formulations. As relatively large volumes may be administered by nebulizers, the solutions must be isotonic and have a pH not lower than 3 and not higher than 8.5. Multidose preparations containing preservatives are available, although generally, sterile, single unit doses without a preservative are used. 31  RECTAL SOLUTIONS Rectal solution )enemas( are usually administered for local or systemic drug action. Enemas can be aqueous or oily solutions. Micro-enemas have a volume of 1 to 20 ml, while macro-enemas have volumes of 50 ml or more. Macro-enemas should be warmed to body temperature before administration. VAGINAL SOLUTIONS Vaginal solutions are administered for local effect, for irrigation or for diagnostic purposes. Vaginal solutions are aqueous. 32 Excipients to adjust pH may be included (3.8-5). OCULAR SOLUTIONS Ocular solutions are used to treat local disorders of the eye, e.g. Infection. Ocular solutions may also be used to treat intraocular disorders, such as glaucoma. Eye lotions are solutions for rinsing or bathing the eye, or for impregnating eye dressings. Most ocular solutions are aqueous. They must be manufactured sterile as the product is to come in contact with tissues that are very sensitive to contamination. Once opened, a multidose ocular product should remain free from viable microorganisms during its period of use and must contain antimicrobial preservatives. The solution pH should be close to physiological pH of tears (pH 7.4) or slightly more alkaline to reduce pH induced lacrimation, irritation and discomfort. Ocular solutions must be isotonic with the tears to minimize irritation and discomfort. An increase in viscosity (15–25 mpa s ) prolongs the solution’s residence in the eye. 33  PARENTERAL SOLUTIONS Parenteral solutions must be sterile and pyrogen-free. Preservatives, such as benzyl alcohol in case multidose products. Intravenous – the solution must be aqueous, as oil droplets can occlude the microcirculation. Intramuscular and subcutaneous – the solution can be aqueous or non-aqueous. Ideally, a parenteral aqueous solution should have a pH close to physiological pH (which is 7.4), to avoid pain, phlebitis and tissue necrosis. Parenteral solutions must be isotonic when large volumes are administered by intravenous infusion. When smaller volumes are used, a wider range of tonicity can be tolerated as dilution with body fluids occurs. 34 REGULATORY ASPECTS AND GUIDELINES FOR SOLUTIONS Regulatory Framework Pharmacopoeial Standards Good Manufacturing Practices Liquid dosage form solutions Pharmacopoeial monographs, are subject to strict regulatory such as those in the United The production of guidelines and requirements, States Pharmacopeia (USP) pharmaceutical solutions such as those set by the FDA, and European Pharmacopoeia must adhere to Good EMA, and other governing (Ph. Eur.), provide detailed Manufacturing Practices bodies. These regulations standards and test methods (GMP) guidelines to ensure cover aspects like for the quality, purity, and the consistency, safety, and manufacturing, packaging, performance of solution efficacy of the final product. labeling, and post-approval dosage forms. This includes controls over changes. facilities, equipment, personnel, and documentation. 36