Pharmaceutical Preparation 1 – Medicinal Solutions

1. Definition of “Medicinal Solution”

A medicinal solution is a pharmaceutical preparation that is prepared by dissolving one or more medicinal substances in a solvent or a mixture of solvents. Medicinal solutions can be used internally (for systemic effects) or externally (for topical effects).

2. Classification of Medicinal Solutions

Medicinal solutions can be classified according to various criteria:

• Based on physicochemical structure:

• True solution: The medicinal substance is completely dissolved in the solvent, forming a homogeneous phase.

• Colloidal solution: The medicinal substance is dispersed in the solvent as colloidal particles (size ranging from 1nm to 1000nm), forming a colloidal dispersion system.

• Macromolecular solution: The medicinal substance is macromolecules, dissolved in the solvent to form a macromolecular dispersion system.

• Based on the state of aggregation:

• Solution of solid in liquid (e.g., sodium chloride solution in water).

• Solution of liquid in liquid (e.g., alcohol solution in water).

• Solution of gas in liquid (e.g., oxygen solution in water).

• Based on the nature of the solvent:

• Aqueous solution: The solvent is water.

• Oil solution: The solvent is vegetable oil or mineral oil.

• Alcoholic solution: The solvent is ethanol or a mixture of ethanol and water.

• Based on the origin of the preparation formula:

• Solution prepared according to the process in the Pharmacopoeia: Pharmaceutical solution.

• Solution prepared according to prescription: Solution prepared according to the doctor’s request.

3. Advantages of Medicinal Solutions

• High bioavailability: Absorbed faster than solid dosage forms.

• Reduced gastric mucosal irritation: Particularly suitable for patients with gastritis.

• Easy to use for children and those with difficulty swallowing: Solutions are easy to administer to children or the elderly.

4. Disadvantages of Medicinal Solutions

• Poor stability of medicinal substances: They can be easily decomposed in a solution environment, especially when exposed to high temperatures or light.

• Environment easily contaminated by microorganisms, bacteria, and fungi: Leading to decomposition of the medicinal substance, reducing treatment effectiveness and potentially harmful to health.

• Bulky, inconvenient for packaging and transportation: Solutions often have larger volumes than solid dosage forms.

• Difficult to mask taste: Some medicinal substances have unpleasant tastes, and solutions are difficult to mask the taste.

• Difficult to accurately divide doses: Accurately dividing doses for solutions can be more difficult than for solid dosage forms.

5. Composition of Medicinal Solutions

Medicinal solutions typically consist of three elements:

• Active ingredient: The main component that has a therapeutic effect on the disease.

• Excipients: Includes the solvent and auxiliary substances that support the active ingredient, ensuring the stability, flavor, color, viscosity, etc. of the medicinal solution.

• Packaging: The material that contains the medicinal solution, ensuring the best drug preservation.

6. Auxiliary substances in medicinal solutions

6.1. Types of auxiliary substances:

• Antioxidants: Protect the medicinal substance from oxidation, keeping the solution stable in color and efficacy.

• For aqueous solutions: Sodium bisulfite.

• For oil solutions: BHA, BHT.

• Solubility enhancers: Help poorly soluble medicinal substances dissolve better in the solvent.

• Surfactants: Help reduce surface tension between the medicinal substance and the solvent.

• Hydrophilic intermediate: Help link poorly soluble medicinal substances with water molecules.

• pH adjusters: Control the pH of the medicinal solution, ensuring that the active ingredient achieves optimal therapeutic efficacy.

• Preservatives: Prevent the growth of microorganisms in the medicinal solution, keeping the drug safe and effective.

• Nipasol, Nipagin, Ethanol > 15%.

• Coloring agents, flavoring agents: Improve the taste and color of the medicinal solution, making it easier to drink.

• Sweeteners: Make the medicinal solution taste sweet and easier to drink.

• Glucose, sorbitol.

6.2. Note:

• Choose the appropriate auxiliary substances based on the medicinal substance and the preparation formula.

• Ensure the optimal concentration of auxiliary substances, which does not affect the efficacy of the medicinal substance and is safe for users.

7. Solvents used in the preparation of medicinal solutions

7.1. Classification of solvents:

• Strong polar solvents: Water, ethanol, glycerin,… dissolve well in polar compounds, such as inorganic salts, sugars, etc.

• Weak or semi-polar solvents: Acetone, chloroform,… dissolve well in weakly polar compounds.

• Non-polar solvents: Ether, paraffin oil, vegetable oil,… dissolve well in non-polar compounds, such as fats, oils, etc.

7.2. 4 most common solvents:

• Water:

• Advantages: Strong polar, dissolves well in many compounds, non-toxic, cheap, easily available.

• Disadvantages: Easy to be contaminated by bacteria, decomposes some medicinal substances.

• Ethanol:

• Advantages: Has antimicrobial properties, dissolves well in some medicinal substances that are poorly soluble in water.

• Disadvantages: Toxic, volatile, flammable.

• Glycerin:

• Advantages: Has antimicrobial properties, dissolves well in some medicinal substances, provides good moisture retention.

• Disadvantages: Easy to absorb moisture, causing skin irritation.

• Vegetable oil:

• Advantages: Dissolves well in oil-soluble substances.

• Disadvantages: Difficult to absorb, easily oxidized.

8. Characteristics of water as a solvent

• Strong polar: Dissolves well in many inorganic and organic compounds (ability to dissolve organic compounds is less than alcohol).

• Acidic water dissolves alkaloid bases; Alkaline water dissolves acids, amphoteric substances, saponins.

• The larger the hydrocarbon radical, the less soluble the organic substances.

• Does not dissolve resins, fats, alkaloid bases.

• Good conductor for various dosage forms.

• Complete release of medicinal substances.

• Does not have any specific pharmacological effect.

• Medicinal substances are easily decomposed, microorganisms, molds easily develop.

9. Types of water commonly used

• Distilled water:

• It is pure water that meets chemical, microbiological, etc. standards.

• Prepared by evaporation and condensation back to liquid.

• Commonly used in the preparation of oral, injectable, and external medications, etc.

• Demineralized water (Ion exchange water):

• It is chemically pure water, prepared by removing chemical impurities by passing ordinary water through an ion exchange resin column.

• Commonly used in the preparation of external medications, oral medications, etc., or as water used in the preparation of medications.

• Reverse osmosis water (RO – Reverse osmosis):

• It is purified water that removes dissolved salts by forcing water through a semi-permeable membrane at high pressure.

• Quite pure, commonly used in the preparation of oral medications, washing water.

10. Distilled water

10.1. Features:

• Distilled water is the main water used in pharmaceutical preparations.

• Meets pure standards in terms of chemistry, microbiology, etc. (According to Pharmacopoeia standards).

• There are 2 types: Ordinary distilled water, distilled water for injection.

10.2. Technique for preparing distilled water:

• It is prepared by evaporation and condensation back to liquid.

10.3. Impurities in water:

• Mechanical impurities: Removed by sedimentation and filtration.

• Organic impurities: Destroyed by potassium permanganate.

• Volatile impurities (ammonia): Boil the water or use alum.

• Inorganic impurities: Such as calcium hydrocarbonate and magnesium hydrocarbonate.

11. Hard water

• It is water containing a large amount of calcium and magnesium salts.

• Hardness depends on the number of milliequivalents of calcium and magnesium ions in one liter of water.

• Hard water contains 6 – 10 mg equivalents of Ca+ and Mg2+ ions in 1 liter.

12. Softening water

• Add a quantity of calcium hydroxide: Remove temporary hardness of water, form precipitate CaCO3, MgCO3.

• Add a quantity of sodium carbonate: Remove permanent hardness, form insoluble carbonate.

13. Demineralized water (Ion exchange water)

13.1. Features:

• It is chemically pure water.

• It does not meet microbiological and organic standards.

13.2. Principle of the method for preparing demineralized water:

• Let the water flow sequentially through the anion exchange column and the cation exchange column or a mixture of these two types of resins.

• There are 2 types of exchange resins:

• Anion exchange resin (R+OH-): Exchange and retain anions.

• Cation exchange resin (R-H+): Exchange and retain cations.

14. Reverse osmosis water (RO)

14.1. Features:

• It is purified water that removes dissolved salts by forcing water through a semi-permeable membrane such as cellulose acetate at high pressure.

• Quite pure (can remove 80 – 98% of dissolved ions, completely remove microorganisms and pyrogens).

15. ALCOHOL

• It is a polar solvent with the -OH group.

• The higher the hydrocarbon chain in the homologous series, the lower the polarity and the miscibility with water.

• The higher the order, the more OH groups, the stronger the polarity than having one -OH group.

16. Ethanol and Ethanol + Water mixture

• Can dissolve: Acids, organic bases, alkaloids and their salts, some glycosides, resins, essential oils, lipids, dyes,…

• Does not dissolve: Pectin, gum, protein, enzyme.

• Forms a mixture at any ratio with water and glycerin.

• Solvent for external medications, oral medications, injections, etc.

17. Advantages and disadvantages of Ethanol

• Advantages:

• Has antimicrobial properties.

• Some medicinal substances are more stable in ethanol.

• Good conductor, rapid and complete absorption of medicinal substances.

• Disadvantages:

• Not completely inert in terms of pharmacology: Inhibits the nervous system, toxic to the liver, causes dependence.

• Volatile, flammable.

• Coagulates albumin, enzymes.

• Easily oxidized.

18. GLYCERIN

• The anhydrous form is easy to absorb moisture and irritate -> Use pharmaceutical glycerin containing 3% water.

• Has antimicrobial effect at a concentration > 20%.

• Miscible with ethanol and water.

• Mainly used in external medications: Helps to retain moisture and adhere well.

19. VEGETABLE OIL

• It is a mixture of glycerides of higher fatty acids. Commonly used peanut oil, castor oil, sesame oil, fish liver oil.

• Non-polar solvent, insoluble in water, soluble in chloroform, ether, petroleum ether.

• Dissolves some organic substances such as: Camphor, menthol, essential oils, alkaloid bases, some oil-soluble vitamins such as A, D, E, K.

• Used as a solvent for nasal drops, ear drops, ointments, etc.

20. Technique for preparing medicinal solutions

20.1. Steps:

1. Weigh or measure medicinal substances and solvents.

2. Dissolve and mix the ingredients.

3. Filter.

4. Package, present the finished products.

20.2. Weighing, measuring medicinal substances and solvents:

• Weigh, measure sufficiently and accurately to ensure the dosage according to the Pharmacopoeia regulations.

20.3. Dissolve and mix the ingredients:

• The order of dissolution should be performed:

• Dissolve poorly soluble, sparingly soluble substances first; easily soluble substances later.

• Prepare the solvent mixture first.

• Solubility enhancers are added before the medicinal substance.

• Use a solvent intermediate: Dissolve the substance in the solvent intermediate first, then slowly add it to the solution.

• Antioxidants, buffer systems, preservatives are dissolved before dissolving with the medicinal substance.

20.4. Filtering:

• Filter the medicinal solution to remove impurities, ensuring that the medicinal solution is clear and homogeneous.

• Choose the appropriate type of filter membrane based on the properties of the medicinal solution.

21. Factors affecting the solubility of solid medicinal substances in solution:

21.1. Chemical nature of solute and solvent:

• Increased solubility:

• Water-loving functional groups -OH, NH2, SH,… in the solute molecule will increase solubility due to increased polarity. For example: Phenol when added with an OH group increases its solubility in water by 100 times compared to benzene.

• Transfer some medicinal substances in weak acid form to salt form, will increase solubility because the salt has greater dissociation.

• Reduced solubility:

• Transfer medicinal substances to esterified forms, reducing decomposition and bitterness such as:

• Chloramphenicol (bitter) is converted to Chloramphenicol palmitate (not bitter).

• Erythromycin (bitter) is converted to Erythromycin propionate (not bitter).

21.2. Temperature:

• Endothermic substances: Solubility increases with increasing temperature.

• Exothermic substances: Solubility decreases with increasing temperature.

• Constant solubility with increasing temperature: NaCl

• Some decrease with increasing temperature: Calciumglycerophosphate, Calcium citrate, Methylcellulose.

• Water-containing crystalline molecules: Temperature and solubility trend in opposite directions due to loss of crystalline water, transforming into anhydrous form -> NaSO4.10H2O solubility increases when t < 32.5oC, above this t solubility will decrease because NaSO4.10H2O dissolves endothermically, NaSO4 exothermically.

21.3. pH factor:

• pH affects solubility related to ionization:

• Weak acids: Barbituric, Phenylbutazone -> pH increases, solubility increases.

• Weak bases: Alkaloids, Clopromazine,… -> pH increases, solubility decreases.

• Amphoteric: Amino acids, Oxytetra,…

• Increasing pH below the isoelectric point reduces solubility, above the isoelectric point increases solubility.

• Note: The stability of the active ingredient: Chloramphenicol.

21.4. Polymorphism:

• Medicinal substances can crystallize in many forms depending on the conditions.

• Different crystalline forms have different structures and solubilities: Ampicillin anhydrous has greater solubility than Ampicillin trihydrate.

• The more stable crystalline form is usually less soluble than the amorphous form: Novobiocin in amorphous form is 10 times more soluble than crystalline form.

21.5. The presence of other substances:

• Electrolytes reduce the solubility of substances.

• Electrolytes need to be diluted in concentration when combined with poorly soluble substances in solution.

• To dissolve quickly, dissolve in order, poorly soluble substances are dissolved first.

22. Dissolution rate

• Noyes and Whitney formula:

• V = dC/dt = D.S. (Cs – Ct)/ h

• D: Diffusion coefficient of the medicinal substance in the solvent.

• S: Surface area of contact between the medicinal substance and the solvent.

• Cs: Saturation concentration of the medicinal substance.

• Ct: Concentration of the medicinal substance at time t.

• h: Thickness of the diffusion layer.

23. Factors affecting dissolution rate

23.1. Contact area:

• Grind medicinal substances finely -> Increase contact surface area (S) -> Increase solubility.

23.2. Temperature and viscosity of the environment:

• Most of the time t increases, the dissolution rate increases:

• Due to the diffusion coefficient of the solute in the solvent increasing (Cs – Ct) increasing -> V increasing.

• Due to the solvent viscosity decreasing -> V increasing.

23.3. Stirring:

• Break down diffusion layers, bring new solvent layers closer to the surface of the solute -> Increase the concentration difference, the thickness of the diffusion layer becomes extremely small -> Increase the dissolution rate.

• Dissolve colloidal substances: Allow colloidal substances to absorb water, swell completely, avoid stirring -> reduce the contact area.

23.4. Solubility of the solute:

• Solubility increases -> Cs increases -> V increases.

24. Per Descensum dissolution method:

• The medicinal substance is sprinkled on the surface of the solvent or the cloth bag is hung submerged in the solvent.

• The medicinal substance will dissolve and form a saturated solution layer.

• This layer has a large specific gravity and moves to the bottom of the vessel, pushing the new solvent layer with a smaller specific gravity to the surface, continuing to dissolve.

• This method is used to dissolve silver colloids or prepare simple sugar syrups.

25. Special dissolution methods:

25.1. Method of creating easily soluble derivatives:

• Principle: Create easily soluble derivatives with poorly soluble medicinal substances in the solvent, this derivative must maintain the biological activity of the medicinal substance.

• Typically Lugol’s solution: KI forms a derivative KI3 (highly soluble in water) with I2 (very poorly soluble in water). The higher the concentration of KI, the faster the reaction rate.

25.2. Using water-loving intermediates:

• Principle: Water-loving intermediates act as an intermediate linking the solvent and the solute.

• Molecules carrying many polar groups such as: -COOH, -OH, NH2, sulfate,… the rest are straight-chain or cyclic hydrocarbon radicals.

• The organic part has affinity for the hydrophobic part of the poorly soluble substance, the hydrophilic function has affinity for water molecules -> electrostatic interaction -> Increase solubility.

• Use in a large proportion (sometimes larger than the amount of substance to be dissolved) -> Treatment disadvantage.

• Examples of methods using water-loving intermediates:

• Sodium benzoate to dissolve Caffeine, Anesthesia.

• Citric acid to dissolve Calcium Glycerophosphate.

• Antipyrine or Uretan to increase the solubility of Quinine.

25.3. Using a solvent mixture:

• Principle: Change the solvent from semi-polar to strongly polar, with a polarity close to the polarity of the poorly soluble medicinal substance in water.

• Commonly used polar solvents: Ethanol, isopropanol, glycerin, propylene glycol, amines such as ethylenediamine,…

• Water – alcohol mixture -> dissolve camphor. Glycerin – alcohol – water mixture dissolves alkaloids.

• Examples of methods using a solvent mixture:

• Bromoform solution has the composition Bromoform – Glycerin – Ethanol, ratio 1:3:6.

25.4. Using surfactants (surface active agents):

• Surfactants are substances that, when dissolved in a solvent, can reduce the surface tension of the phase separation.

• The structure consists of 2 parts: Water-loving part and oil-loving part.

• Condition: The concentration of the surfactant is higher than the critical micelle concentration.

• The mechanism by which surfactants increase solubility is to absorb the solute into the micelles.

• TWEEN is a commonly used surfactant (Tween 20 or 80). Use to dissolve essential oils in water to prepare fragrant water.

• It has an unpleasant taste (oral medication, should not be used in excess of 3%), reduces the efficacy of some medicinal substances.

26. Critical micelle concentration:

• It is the concentration at which surfactant molecules aggregate to form micelles (clusters) and the solution becomes a colloidal solution.

27. Alteration and stabilization of medicinal solutions

27.1. Causes:

• Medicinal substances during preparation undergo physicochemical influences that make them in a thermodynamically unbalanced state, medicinal substances in solution are in a molecularly dispersed state, so reactions occur very easily.

• It is difficult to completely eliminate decomposition.

27.2. Classification of alterations:

1. Physical alterations.

2. Chemical alterations.

3. Biological alterations (microorganism contamination).

27.3. Physical alterations:

• Include phenomena:

• Precipitation.

• Coagulation of colloids.

• Discoloration or color change.

27.3.1. Precipitation:

• Concentrated solution with easily volatile solvent.

• Precipitation due to salification occurring when easily soluble substances are added to solutions of poorly soluble substances.

• Ion exchange reaction creates poorly soluble substances when the environment changes, impurities are released from the packaging,…

27.3.2. Coagulation of colloids:

• Depends on the nature and concentration of the colloid.

• The presence of promoting agents such as electrolytes, pH,…

• The aging phenomenon of colloids in alcohol, liquid extract,…

• Cause changes in viscosity, color.

27.3.3. Discoloration or color change:

• Chemical changes cause discoloration or color formation.

• Give the impression of instability of the preparation.

27.4. Chemical alterations:

• Change sensory, physical properties.

• Reduce or eliminate the therapeutic effect of the preparation.

• Create toxic or side-effect degradation products.

• Includes:

• Oxidation-reduction reactions.

• Hydrolysis reactions.

• Racemization reactions.

• Complex formation reactions.

27.4.1. Oxidation-reduction reactions:

• Oxidation-reduction reactions are chemical reactions involving the exchange of electrons between substances.

• Medicinal substances are easily oxidized in air, light, high temperatures.

• Antioxidants are used to protect medicinal substances from oxidation.

27.4.2. Hydrolysis reactions:

• Hydrolysis reactions are chemical reactions in which medicinal substance molecules are decomposed by water.

• Medicinal substances are easily hydrolyzed in acidic or alkaline environments.

• Preservatives are used to prevent hydrolysis reactions.

27.4.3. Racemization reactions:

• Racemization reactions are chemical reactions in which one enantiomer of the medicinal substance is converted to the opposite enantiomer.

• Medicinal substances are easily racemized in acidic or alkaline environments.

• Storage conditions such as temperature, light can affect the racemization rate.

27.4.4. Complex formation reactions:

• Complex formation reactions are chemical reactions in which medicinal substances form complexes with metal ions in the environment.

• Medicinal substances are easily complexed in environments containing metal ions.

• Chelating agents are used to prevent complex formation reactions.

27.5. Biological alterations (microorganism contamination):

• Medicinal solutions are easily contaminated with bacteria and fungi during production, storage, or use.

• Microorganisms can decompose medicinal substances, creating toxic products.

• Preservatives are used to prevent the growth of microorganisms.

28. Ways to stabilize medicinal solutions:

• Choose the appropriate solvent: The appropriate solvent will help stabilize the medicinal substance in the solution.

• Use suitable auxiliary substances: Auxiliary substances will help protect the medicinal substance, prevent decomposition and maintain the properties of the medicinal solution.

• Adjust pH: Adjusting the pH of the medicinal solution to the optimal level helps stabilize the medicinal substance.

• Store medication properly: Store medication at appropriate temperature, light, and humidity.

• Use suitable packaging: Suitable packaging will help preserve the medication better, preventing contamination or decomposition.

29. Note:

• When preparing medicinal solutions, strictly comply with the regulations on pharmaceutical preparation techniques, ensuring food safety.

• Use medicinal solutions in a short period of time, avoid leaving the medication for too long, especially when the medication has been opened.

• Always read the instructions carefully before using the medication, consult a doctor or pharmacist when necessary.

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