Name: Pharmaceutical Dosage Chapter 13: Solutions Solutions y Liquid preparations containing one or more chemical substances dissolved

in a suitable solvent or mixture of mutually miscible solvents y Prepared from a combination of solid, liquid, and gas y According to use: oral, otic, ophthalmic, or topical y According to composition:  Syrups: aqueous solutions containing sugar  Elixirs: sweetened hydroalcoholic solutions  Spirits: solutions of aromatic materials  Tinctures or fluid extracts: active constituents from crude drugs  Tincture: alcoholic or hydroalcoholic  Injections: parenteral preparations (sterile and pyrogen-free) Preparations where the medicinal agents are intended to provide systemic effects:  Oral solutions, syrups, elixirs, spirits and tinctures  Absorption is rapid than suspension or solid dosage forms of the same medicinal agent  Information utilized in formulation or compounding a pharmaceutical solution:  Solubility and stability of solutes to the solvent  Avoided in the formulation or compounding:  Combination of medicinal or pharmaceutical agents resulting in chemical or physical interactions affecting therapeutic quality or stability Solubility y Attractive forces between atoms:  Lead to formulation of molecules and atoms y Attractive forces between molecules:  Causes them to cohere  Like dissolves like y Dipole-dipole or Vander Waals forces  Associated with the weak reactions y Saturated solution  When a solvent at a given temperature has dissolved all of the solute y Increase in temperature (important factor) increases solubility y Factors affecting solubility  Temperature, pressure and pH, particle size and extent of agitation y Positive heat of solution  Chemicals absorb heat when they are dissolved resulting in increased solubility with increased temperature y Negative heat of solution  Decrease in solubility with a rise in temperature y Solubility expressed as grams of solute dissolving in mL of solvent (g/mL) Kinds of Solutions y Aqueous  Water-based, water as main solvent y Non-aqueous  Not water but another solvent  Hydroalcoholic: alcohol as main solvent o Elixirs and spirits  Oleaginous: oil as main solvent o Liniment and toothache drops  Ethereal: ether as the main solvent o Collodion Solvent for Liquid Preparations y Alcohol, USP: Ethyl A lcohol, ethanol (94.9 96.0% ethanol by volume) y

Most useful solvent next to water Hydroalcoholic mixture with water Miscible with water Dissolve other water-insoluble ingredients Used with other solvents: glycols and glycerin to reduce the amount of alcohol required  Antimicrobial preservative  Toxic effects when ingested in pharmaceutical products by children  Recommended by the content for OTC drugs:  6 to 12 yrs. Of age: 0.5%  Over 12 yrs.: 5%  Adults: 10% y Diluted A lcohol, NF (49%)  Produced by mixing equal amount of water and alcohol  Upon mixing the volume is 3% less because liquids contract  Hydroalcoholic solvent in pharmaceutical processes and preparations y Rubbing Alcohol (79% ethyl alcohol)  Other components: denaturants with or without color additives, perfume oils, and preservatives  Composed of 8 parts of volume of acetone, 1.5 parts of methyl iso-butyl ketone, and 100 parts of ethyl alcohol  Denatorium benazoate is added to prevent accidental or abusive ingestion  Use: rubefacient, soothing rub, germicide, skin cleaner, vehicle  Synonym: alcohol rubbing component y Glycerin, USP  Clear, syrupy liquid with a sweet taste  Miscible with water and alcohol  With its viscosity: solutes are slowly soluble  Not mixed with oxidizing agents (KMnO4, KClO3): will form an explosive combination  Preservative, stabilizer and auxiliary solvent, internal preparations y Isopropyl Rubbing Alcohol  70% by volume isopropyl alcohol and the remainder  Denaturants with or without color additives, perfume oils and stabilizers  Rubefacient, soothing rub, vehicle, preparing needles and syringes (diabetic patients) for hypodermic injections of insulin and skin disinfectant y Propylene Glycol, USP  Viscous liquid miscible with water and alcohol  Useful solvent and substitute for glycerin Solvent for Liquid Preparation y Purified Water, USP  Naturally occurring water exerts solvent effect on most substance it contacts (impure) containing amount of:  Dissolved inorganic salts: Na, K, Ca, Mg, Fe, Cl, SO 4, & HCO3  Dissolved and undissolved organic mater  Microorganisms  Obtained by distillation, ion exchange, and reverse osmosis  Ion exchange o Makes use of filter membranes in removing contaminants o Advantages over distillation: permit ease of operation, minimal maintenance, and more mobile facility  Reverse Osmosis o Pressurized steam of water is passed parallel to the     

inner side of membrane core

filter

Preparation of Solution y Most pharmaceutical preparation solutions  Unsaturated with solute y The strengths of pharmaceutical preparations  Expressed in % strength  For very dilute preparations ration strengths y Several techniques to hasten dissolution  Applying heat  Reducing the particle size of the solute  Using a solubilizing agent  Subject the ingredients to vigorous agitation y Solutions intended for oral administration contain  Flavorants and colorants  When needed:  Stabilizers of medicinal agents  Preservative (prevents growth of microorganisms) Oral Solutions and Preparation for Oral Solution y Dry mixtures for solution or reconstitution  Number of medicinal agents (antibiotics) with insufficient stability in aqueous solution to meet extent shelf-life periods  7-14 days: expiration date after filling with a suitable solvent Example:  Cloxacilin Sodium for Oral Solution, USP o Anti-infective  Penicillin V Potassium for Oral Solution, USP o Anti-infective  KCl for Oral Solution, USP o K Supplement y Oral solutions  Pediatric form of an adult product  Reconstituting a dry powder mixture/extemporaneously compound an oral solution from bulk components y Oral rehydration solutions  Rapid fluid loss associated with diarrhea lead to:  Dehydration  Ultimately death in some patients particularly the infants  Effective in treatment of patients with mild volume depletion 3 to 10% of body weight  OTC, inexpensive and use diminished the incidence of complications associated parentally administered electrolytes solution  Typical oral rehydration solution contains:  45 mEq Na, 20 mE q Cl, 30 mE q Citrate and 25 g dextrose  Never mixed with or given with other electrolyte-containing liquids:  Milk  Fruits  Commercial oral electrolyte solution:  Prevents dehydration or achieve rehydration Examples: o Pedialyte solution o Rehydrate solution y Oral colonic lavage solution  Administration of oral laxative:  Magnesium citrate or bisacodyl the night before  Cleansing enema administered 2 to 4 hours prior to the procedure

y Syrups y

Alternative method to prepare the gastrointestinal tract:  Requires less time and dietary restriction and obviates cleansing enemas  Entails oral administration of: balanced solution of electrolytes with PEG  Adult dose: 4L, 240 ml per 10 minutes until 4L is achieved Magnesium citrate oral solution  Citrate or citrate of magnesia  Colorless to slightly yellow clear effervescent liquid, sweet acidulous taste and lemon flavor  Excellent medium for the growth of molds and any molds spores: must be killed to remain stable  Always been troublesome:  Tendency to deposit a crystalline solid upon standing Sodium citrate and citric acid oral solution  Contains sodium citrate 100 mg and citric acid 67 mg in each millimeter of aqueous solution 

Concentrated aqueous preparations of a sugar or sugar substitute with or without flavoring agents and medicinal substances y Serves as:  Pleasant tasting vehicle for medicinal substances in:  Extemporaneous compounding of prescription  Preparation of a standard formula for a medicated syrup y Commercially prepared medicated syrups:  By combining:  Sucrose  Purified water  Flavoring  Coloring agents  The therapeutic agent  Other ingredients y Clear aqueous saturated solution of sugar commonly sucrose y 1.313: specific gravity y 85%w/v or 65%w/w y High osmotic pressure y Maybe:  Medicated: with active ingredient  Non-medicated Components of Syrup y Sucrose or sugar substitute  Provide sweetness and viscosity y Antimicrobial preservatives y Flavorants y Colorants Sucrose Based and Non-sucrose B ased Syrups: y Sucrose: sugar most frequently employed in syrups  Special circumstances: replaces by other sugar substances:  Sorbitol  Glycerin  Prophylene glycol y Replaced by nonglycogenetic substances  Methylcellulose or hydroxyl ethylcellulose y Most syrups contain 60 to 80% sucrose y Efficient nutrient medium for growth of microorganisms y Concentrated sugar solution  Resistant to microbial growth y Syrup NF 26 (Simple Syrup) prepared by:

Dissolving 85g of sucrose in purified water to make 100 ml of syrup Antimicrobial Agent y The amount of preservative  Varies with the proportion of water available for growth:  Benzoic acid: 0.1-0.2%  Sodium Benzoate: 0.1-0.2%  Methylparabens, proplyparabens and butylparabens, totaling to 1% Flavorant y Synthetic flavorant or with naturally occurring materials such as volatile oils (e.g. orange oil), vanillin, and others Colorant y Enhance the appeal of the syrup y Correlates with the flavorant employed Method of Preparation of Syrups y Solution of the ingredients with the aid of heat (fastest) y Solution of the ingredients with agitation without the use of heat, or the simple admixture of liquid components (slowest) y Addition of sucrose to a prepared medicated liquid or to a flavored liquid 

Percolation of either the source of medicating substance or of the sucrose Solution with the Aid of Heat y Sugar added to the purified water and heat is applied y Syrup when overheated  Becomes amber colored as the sucrose caramelizes  Excessive heating convert syrups into its inversion form (Excessive heat Inversion Caramelization) y Medicinal agents destroyed by elevated temperature Solution by Agitation Without Aid of Heat y Dissolves with purified water  Ingredients in a vessel larger than the volume of syrup to be prepared permitting thorough agitation of the mixture Addition of Sucrose to a Medicated Liquid or to Flavored Liquid y Alcohol-soluble components  Undesirable or unnecessary components of corresponding syrup  Removed by mixing the tincture or fluid extract with water y

Table 13.5: Examples of Oral Solutions by Category Oral Solution Antidepressant Nortriptyline HCl Pamelor (Novartis) Oral Solution 10mg nortriptyline/5ml Tricyclic antidepressant Representative Commercial Products Concentration of Commercial Product Comments

Fluoxetine HCl Antiperistaltic

Prozac Liquid (Dista)

20mg fluoxetine/5ml

For depression, obsessive compulsive disorder

Diphenoxylate atropine sulfate

HCl,

Lomotil Liquid (Searle)

2.5mg diphenoxylate HCl, 0.025mg atropine sulfate/5ml

For diarrhea. Diphenoxylate is related structurally and pharcologically to the opioid meperidine. Atropine sulfate in subtherapeutic amounts discourages (by virtue of side effects) deliberate overdosage

Loperamide HCl

Imodium A -D Liquid (McNeil Consumer Products)

1mg loperamide HCl/5ml

For diarrhea in adults and children aged 6 years and older. Structurally related to haloperidol.

Antipsychotics Haloperidol Perphenazine Haloperidol Oral Solution Perphenazine Oral Solution Thiothixene HCl Bronchodilator 2mg haloperidol/ml 16mg perphenazine/5ml Navane concentrate (Pfizer) Primarily for severe neuropsychiatric conditions when oral medication is preferred and tablets and capsules are impractical. Concenreted solutions used by adding desired amount of concentrate bt calibrated dropper to soup or a beverage.

Theophylline

Theophylline (Roxane)

Oral

Solution

80mg theophylline/15ml

Alcohol-free solution for treatment of bronchial asthma and reversible bronchospasm associated with chronic bronchitis and emphysema.

Cathartics Magnesium USP Citrate, Magnesium citrate equivalent to 1.55-1.9 g/100ml magnesium oxide

Discussed in text.

Sodium phosphate

Phospho-Soda (Fleet)

2.4g monobasic sodium phosphate, 0.9g dibasic sodium phosphate/5ml

Corticosteroid

Prenisolone phosphate

sodium

Pediapred (Medeva)

Oral

Solution

5mg prednisolone phosphate)/5ml

(as

sodium

Synthetic adrenocortical steroid with mainly glucocorticoid properties indicated for endocrine, rheumatic, collagen, allergic, and other disorders.

Dental protectant

caries

Sodium fluoride

Pediaflor Drops (Boss)

0.5 mg/ml

Prophylaxis of dental caries; for use when community water supply is inadequately fluoridated.

Electrolyte replenisher

Potassium chloride

KaoChlor 10% Liquid ( Adria)

20 mE q KCl/15ml aqueous vehicle

in

flavored

For hypopotassemia (low blood level of potassium). Condition may be prompted by severe or chronic diarrhea, low dietary intake of potassium, increased renal excretion of potassium, other causes. Solution is diluted with water or fruit juice.

Fecal softener Usually 50-200mg measured by calibrated dropper, mixed with milk, fruit juice, other liquid to mask taste. Softens fecal mass by lowering surface tension, permitting normal bowel habits, particularly in geriatric, pediatric cardiac, obstetric, and surgical patients. Taken for several days or until bowel movements are normal.

Docusate sodium

Colace syrup (Shire)

10mg docusate sodium/ml

Hematinic

Ferrous sulfate

Fer-In-Sol Drops Johnson Nutritional)

(Mead

15mg/0.6ml

For prevention and treatment of iron deficiency anemias. Usual propylactic dose 0.3 or 0.6ml, measured by calibrated dropper, mixed with water or juice. Dosage for intended primarily for infants and children.

Histamine H2 antagonist

Cimetidine HCl

Tagamet HCl Liquid (SmithKline Beecham)

300mg/ml

For peptic ulcer disease, hypersecretory conditions, ZollingerEllison syndrome.

pathologic e.g.,

Opioid agonist analgesic For relief of severe pain; detoxification, maintenance treatment of opioid addiction.

Methadone HCl

Methadone HCl (Roxane)

1 or 2 mg/ml

Vitamin D

Ergocalciferol

Calciferol Drops (Schwarz)

8,000 U/ml

Water-insoluble ergocalciferol (vitamin D2) in propylene glycol. Usual propylactic dose about 400U; therapeutic dose may be as high as 200,000-500,000 U daily in treating rickets.