Lecture 1 (Solutions)_240824_182706.pdf

Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1) Pharmaceutical solutions Pharmaceutical solutions are “liquid preparations contain one or more chemical substances dissolved in one solvent or a mixture of solvents. The Co...

Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1) Pharmaceutical solutions Pharmaceutical solutions are “liquid preparations contain one or more chemical substances dissolved in one solvent or a mixture of solvents. The Common Types of pharmaceutical solutions  Solutions: they contain drugs that are dissolved in an aqueous solvent.  Syrups: they are aqueous solutions containing more than 60% (60 – 85%) of sugar (sucrose).  Elixirs: they are sweetened hydroalcoholic solutions (water + ethanol).  Spirits: they are solutions of aromatic materials in alcoholic solvent.  Tinctures: they are alcoholic or hydroalcoholic solutions prepared by extracting active constituents from crude materials (plant or animal sources).  Pharmaceutical solutions are given by all routes of administration, including:- 1. Oral 2. Parenteral 3. Ophthalmic 4. Nasal 5. Pulmonary 6. Transdermal Advantages and Disadvantages of Pharmaceutical Solutions The Advantages  They usually provide systemic effects.  They have faster absorption into the systemic circulation compared to suspensions or solid dosage forms (tablets or capsules). 1 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1)  The drug is evenly distributed throughout the formulation.  The Irritation of irritating drug is reduced by the administration of its pharmaceutical solution The Disadvantages  Their transport and storage are difficult compared to the solid dosage forms.  The stability of ingredients (drug or excipients) in aqueous solution is often reduced.  They are commonly required to contain a preservative.  The accurate dose depends on the patient’s ability.  The taste of drug is more pronounced in a solution than in solid dosage forms. Formulation of Pharmaceutical Solutions In formulation of pharmaceutical solutions, the pharmacists must take care of two fundamental considerations:- 1) Solubility and 2) Stability 1) Solubility Considerations of Pharmaceutical Solutions The solubility indicates the maximum amount of drug that can be dissolved in a solvent. There are two types of pharmaceutical solutions; aqueous solutions and non-aqueous solutions. However, the most common types are the aqueous pharmaceutical solutions. Aqueous Solutions Water is the most widely used as a solvent for preparation of pharmaceutical solutions, because of its availability, physiological compatibility and void of toxicity. Types of Pharmaceutical Water 1. The purified water or distilled water (DW) is water free from the dissolved ions and metals (Fe, Na, Cu, Al, etc….). 2 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1) The distilled water is generally prepared by:- distillation deionization the process of reverse osmosis Diagrammatic representation of osmosis and reverse osmosis 2. Water for Injection (WFI) that is used for the parenteral, ophthalmic and nasal solutions. The WFI is obtained by sterilizing the DW using the autoclave. 3. Carbon dioxide-free WFI that is used for drugs which are sensitive to the carboxylation by CO2, such as phenobarbitone sodium or aminophylline. 4. Air-free WFI that is used for drugs which are liable to oxidation, such as morphine and ergotamine.  Tip: CO2-free WFI and Air-free WFI are obtained by boiling for at least 10 minutes. 3 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1) Improvement of Drug Solubility For some drugs, their dose is larger than their solubility, requiring using one of the approaches of improvement of drug solubility that include:-  Co-solvency - The weak electrolytes or non-polar drugs are often poorly water-soluble. - The solubility of these drugs can be improved by addition of another solvent that is miscible with water. This solvent is called co-solvent. - The most co-solvent used widely are ethanol, glycerol, propylene glycol, isopropanol and PEG-400. Examples: 1) the solubility of Cotrimoxazole is improved in a mixture of propylene glycol and water. 2) Paracetamol is formulated as an elixir using alcohol, propylene glycol and syrup. 3) Betamethasone valerate is dissolved in a water/isopropyl alcohol mixture.  Control of the Solution pH The solubility of drugs that are weak electrolytes (acids or bases) is often poor and is dependent on the pH of solution. - The solubility of a weak base can be increased by lowering the pH of solution, whereas the solubility of a weak acid can be improved by increasing the pH. - The chosen pH to improve the drug solubility must do not conflict with other components and affect their stability. To maintain the pH of solutions at the desired value, buffers should be used such as carbonate, acetate, phosphate, glutamate and borate buffers. 4 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1)  Solubilization 1) Using Surface-Active Agents (Surfactants) The solubility of hydrophobic drugs in water may be improved by the addition of a surface- active agent. The mechanism involves the formation of micelles when the concentration of surfactant becomes at critical micelle concentration (CMC). This method is called the micellar solubilization and it is widely used for the formulation of pharmaceutical solutions. In aqueous systems, hydrophobic drugs (non-polar) will dissolve in the interior of micelles (hydrophobic core), which consists of the lipophilic hydrocarbon chains. Examples of surfactants: Tweens and Poloxamers. For example, the solubilization of fat-soluble vitamins such as vitamin K1 is improved using polysorbates (Tweens). 5 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1) 2) Using Cyclodextrins These compounds are molecules of glucose that form circular structures resembling hollow cylinders. Their inner surface is hydrophobic, where hydrophobic drugs can reside. The outer surface of cyclodextrin is hydrophilic that make them freely soluble in water. In general, there are three natural cyclodextrins, the a, β and γ-cyclodextrin, the ring structures of which are composed of 6, 7 and 8 glucose units, respectively (the figure below). Poorly soluble drugs of appropriate size enter into the interior of cyclosextrins, forming soluble inclusion complexes, usually with one 'host' molecule per cyclodextrin molecule. 6 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1) Examples of marketed drugs formulated with cyclodextrins include a range of prostaglandins and the antifungal drug itraconazole.  Complexation In some cases, the poorly soluble drug can be interacted with a water-soluble molecule forming a soluble intermolecular complex. However, the formation of this complex should be reversible, allowing the free drug to be released for offering its therapeutic effect. For example, the complexation of iodine with a 10-15% solution of povidone (povidone iodine) has improved the aqueous solubility of iodine (I2). 7 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1)  Chemical Modification Chemical modification of a drug may be necessary to produce a water-soluble derivative. The chemical modification must don’t reduce the therapeutic effect of drug. Examples include the synthesis of the sodium phosphate salts of hydrocortisone, prednisolone and betamethasone, as follows: 1- Derivatization of these drugs using phosphoric acid that insert the phosphoric group. 2- Preparation of their sodium salts that are water-soluble. 8 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1) 2) Stability Considerations of Pharmaceutical Solutions The pharmaceutical solutions must retain its same physical, chemical and microbiological properties that it possessed at the time of its manufacture. In general, drug substances decompose as a result of the effects of heat, oxygen, light and moisture.  The physical stability is represented by colour, clarity, viscosity, odour, taste that must not change.  For chemical stability, many drug molecules undergo chemical reactions, such as, hydrolysis, oxidation and reduction which are the most common. The poor chemical stability of dosage forms leads to the loss of drug molecules that reduces the efficacy of drug product and may increase the toxicity of product. For example, - Isoniazid degrades into hydrazine, which has carcinogenic properties. - Chloramphenicol degrades by the light into p-nitrosanilline, which is carcinogenic. - Paracetamol hydrolyses into aminophenol, which in turn oxidises into toxic chinonimines. Factors Stimulating Chemical Degradation of Drugs 1) in solutions where the drug is present as molecules 2) Temperature of transportation and storage 3) pH values of pharmaceutical solutions (Buffers) 4) the presence of UV light (amber glass containers) 5) the presence of metals which act as a oxidation catalysts (antioxidants and/or chelating agents) Therefore,  Pharmaceutical solutions are therefore formulated at the pH favored for the good drug stability, and include excipients that enhance product stability (e.g. buffers, antioxidants). 9 Pharmaceutics 1 PhD. Khaled Sh. Shamarekh CONVERTS A DRUG INTO A MEDICINE Lecture (1) To reduce photo-oxidation, solutions are packaged in opaque containers that prevent the transmission of UV light (e.g amber glass containers). To reduce oxidation, antioxidants and/or metal chelators (where heavy metal ions catalyze oxidation) are used. For the microbiological stability, the product should remain sterile (injections, eye drops, etc.) or resistant to microbial growth (oral or external topical solutions). 10