Pharmaceutical Preparation 1 – Pharmaceutical Solutions

1. Definition of “Pharmaceutical Solutions”

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

2. Classification of Pharmaceutical Solutions

• By physicochemical structure:

• True solutions: The medicinal substance is uniformly dispersed in the solvent in the form of molecules or ions.

• Colloidal solutions: The medicinal substance is dispersed in the solvent in the form of colloidal particles, with particle sizes ranging from 1nm to 1µm.

• Macromolecular solutions: The medicinal substance is dispersed in the solvent in the form of large molecules, with particle sizes larger than 1µm.

• By state of aggregation:

• Solutions of solids in liquids: For example, salt in water.

• Solutions of liquids in liquids: For example, alcohol in water.

• Solutions of gases in liquids: For example, CO2 gas in water, forming carbonated beverages.

• By nature of the solvent:

• Aqueous solutions: The medicinal substance is dissolved in water.

• Oily solutions: The medicinal substance is dissolved in oil.

• Alcoholic solutions: The medicinal substance is dissolved in alcohol.

• By the source of the formulation:

• Solutions prepared according to the procedure in the Pharmacopeia: For example, pharmaceutical solutions.

• Solutions prepared according to prescriptions: Prescribed by a doctor and prepared by a pharmacist.

3. Advantages of Pharmaceutical Solutions

• High bioavailability: Absorbed faster compared to solid dosage forms.

• Reduced irritation of the gastric mucosa: Easier for patients who have difficulty swallowing, especially children.

• Ease of use: Easy to adjust dosage.

• Convenient packaging and transportation.

4. Disadvantages of Pharmaceutical Solutions

• Poor stability of the medicinal substance: Easily decomposed in solution.

• Susceptible to microbial contamination: Bacteria and mold can easily grow in a solution.

• Bulky and inconvenient packaging and transportation: Easy to break, spill, or leak.

• Difficult to mask taste: Some medicinal substances have unpleasant tastes.

• Difficult to accurately divide doses: For small doses.

5. Composition of Pharmaceutical Solutions

• Active ingredient: The main component of the pharmaceutical solution, with pharmacological effects.

• Excipients: Auxiliary substances that help with dissolution, preservation, stability, and improving the properties of the solution.

• Solvent: The liquid that dissolves the medicinal substance.

• Additives: Antioxidants, solubilizers, pH adjusters, preservatives, colorants, flavorings, sweeteners, etc.

• Packaging: Glass jars, plastic bottles, syringes, etc.

6. Additives in Pharmaceutical Solutions

• Antioxidants: Prevent the oxidation of the medicinal substance.

• For aqueous solutions: Sodium bisulfite, sodium metabisulfite, etc.

• For oily solutions: BHA (Butylated hydroxyanisole), BHT (Butylated hydroxytoluene), etc.

• Solubilizers: Help dissolve poorly soluble medicinal substances in the solvent.

• Surfactants: Tween 20, Tween 80, etc.

• Hydrophilic intermediates: Propylene glycol, glycerin, etc.

• pH adjusters: Adjust the pH of the solution to ensure the stability and bioavailability of the medicinal substance.

• Preservatives: Prevent the growth of microorganisms.

• Nipasol, Nipagin, Ethanol > 15%, etc.

• Colorants: Improve the aesthetic appearance of the solution.

• Flavorings: Mask unpleasant tastes of the medicinal substance.

• Sweeteners: Enhance the palatability of the solution.

• Glucose, sorbitol, etc.

7. Solvents Used to Prepare Pharmaceutical Solutions

• Strong polar solvents: Dissolve polar compounds well.

• Water, Ethanol, Glycerin, etc.

• Weak or semi-polar solvents: Dissolve less polar compounds well.

• Acetone, Chloroform, etc.

• Non-polar solvents: Dissolve non-polar compounds well.

• Ether, Paraffin oil, Vegetable oil, etc.

8. Four Most Commonly Used Solvents

• Water:

• A strong polar solvent, dissolves inorganic compounds and some organic compounds well.

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

• It does not dissolve resins, fats, or alkaloid bases.

• A good vehicle for various dosage forms.

• Complete release of the medicinal substance.

• No inherent pharmacological effects.

• The medicinal substance is easily decomposed, microorganisms and mold can easily grow.

• Ethanol:

• Has antiseptic properties.

• A good solvent for many medicinal substances.

• A good vehicle, rapidly and completely absorbs the medicinal substance.

• Glycerin:

• Has antiseptic properties at concentrations > 20%.

• Miscible with ethanol and water.

• Mainly used in topical medications: Helps retain moisture and improve adhesion.

• Vegetable oil:

• A mixture of glycerides of higher fatty acids. Commonly used: Peanut oil, castor oil, sesame oil, cod liver oil.

• A 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 like A, D, E, K.

• Used as the basis for nasal drops, ear drops, ointments, etc.

9. Characteristics of Water as a Solvent

• Strong polarity: Dissolves inorganic and organic compounds well (for organic compounds, its dissolving ability is lower than alcohol).

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

• The larger the hydrocarbon chain, the lower the solubility of organic substances.

• Does not dissolve resins, fats, or alkaloid bases.

• A good vehicle for various dosage forms.

• Complete release of the medicinal substance.

• No inherent pharmacological effects.

• The medicinal substance is easily decomposed, microorganisms and mold can easily grow.

10. Types of Water Commonly Used

• Purified water: Chemically, microbiologically, etc. pure water (according to the Pharmacopeia standards). Depending on the dosage form, there are two types: regular purified water, injectable purified water.

• Deionized water (Ion exchange water): Chemically pure water obtained through the removal of chemical impurities by passing regular water through an ion exchange resin column.

• Reverse osmosis water (RO): Purified water that removes dissolved salts by forcing water through a semi-permeable membrane, such as cellulose acetate, at high pressure (140 kf/cm2).

11. Purified water

• Technique for preparing purified water: Prepared by vaporization and condensation.

• Impurities present in water:

• Mechanical impurities: Removed by sedimentation and filtration.

• Organic impurities: Destroyed using Potassium permanganate.

• Volatile impurities (ammonia): Boiling water or using alum.

• Inorganic impurities such as: Calcium bicarbonate and Magnesium bicarbonate.

12. Hard Water

• Water containing a high amount of calcium and magnesium salts.

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

• Hard water contains 6 – 10 mg equivalents of Ca2+ and Mg2+ ions per liter.

13. Softening Water

• Adding a quantity of Calcium hydroxide: Removes temporary hardness of water, forming precipitates of CaCO3 and MgCO3.

• Adding a quantity of Sodium carbonate: Removes permanent hardness, forming insoluble carbonates.

14. Deionized Water (Ion Exchange Water)

• Principle of deionized water preparation: Water is passed sequentially through an anion exchange column and a cation exchange column, or a mixture of both types of resins.

• Anion exchange resin (R+OH-): Exchanges and retains anions.

• Cation exchange resin (R-H+): Exchanges and retains cations.

• Characteristics of deionized water: Achieves high chemical purity standards, but does not guarantee microbiological and organic substance standards. It is often used to prepare external medications, oral medications, etc., or as water for preparing medications.

15. Reverse Osmosis Water (RO)

• Characteristics of reverse osmosis water: Quite pure (can remove 80 – 98% of dissolved ions, completely removes microorganisms and pyrogens). Used for preparing oral medications, rinse water.

16. Alcohol

• A polar solvent with a -OH group.

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

• Higher alcohols with many OH groups are more polar than those with one -OH group.

17. Ethanol and Ethanol + Water Mixtures

• Soluble: Acids, organic bases, alkaloids and their salts, some glycosides, resins, essential oils, lipids, dyes, etc.

• Insoluble: Pectin, gums, proteins, enzymes.

• Forms mixtures at any ratio with water and glycerin.

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

18. Advantages and Disadvantages of Ethanol

• Advantages:

• Antiseptic properties.

• Some medicinal substances are more stable in ethanol.

• A good vehicle, rapidly and completely absorbs the medicinal substance.

• Disadvantages:

• Not completely inert pharmacologically: Inhibits the nervous system, toxic to the liver, can lead to dependence.

• Easily evaporates, flammable.

• Coagulates albumin and enzymes.

• Easily oxidized.

19. Glycerin

• Anhydrous form easily absorbs moisture and causes irritation -> Use pharmaceutical glycerin containing 3% water.

• Has antiseptic properties at concentrations > 20%.

• Miscible with ethanol and water.

• Mainly used in topical medications: Helps retain moisture and improve adhesion.

20. Vegetable oil

• A mixture of glycerides of higher fatty acids. Commonly used: Peanut oil, castor oil, sesame oil, cod liver oil.

• A 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 like A, D, E, K.

• Used as the basis for nasal drops, ear drops, ointments, etc.

21. Technique for Preparing Pharmaceutical Solutions

1. Weigh or measure the medicinal substance and solvent.

2. Dissolve and combine the components.

3. Filter.

4. Package and present the products.

22. 1. Weighing and Measuring the Medicinal Substance and Solvent

• Weigh and measure accurately to ensure the dosage of the medication according to the Pharmacopeia standards.

23. 2. Dissolving and Combining the Components

• The order of dissolution should be:

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

• Prepare the solvent mixture first.

• Add solubilizers before the medicinal substance.

• Use an intermediate solvent: Dissolve the substance in an intermediate solvent first, then slowly combine it into the solution.

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

24. 3. Filtration

• Use filter paper or other filtration methods to remove insoluble solid impurities.

25. Factors Affecting the Solubility of Solid Medicinal Substances in Solution

1. Chemical nature of the solute and solvent.

2. Temperature.

3. pH.

4. Polymorphism, solvation.

5. Presence of other substances.

26. 1. Chemical Nature of the Solute and Solvent

• Increased solubility:

• The presence of hydrophilic functional groups -OH, NH2, SH, etc. in the molecule of the solute will increase solubility due to increased polarity. Phenol, when containing an additional OH group, increases its solubility in water 100 times compared to benzene.

• Converting some medicinal substances from weak acids to salts will increase solubility because salts have greater dissociation.

• Decreased solubility: Converting the medicinal substance to an ester form, limiting decomposition and bitterness, such as:

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

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

27. 2. Temperature

• Endothermic substances: Increased solubility with increased temperature.

• Exothermic substances: Decreased solubility with increased temperature.

• Solubility does not change with increased temperature: NaCl.

• Some decrease when temperature increases: Calcium glycerophosphate, Calcium citrate, Methyl cellulose.

• Crystalline molecules containing water of crystallization: Temperature and solubility tend to be inversely proportional due to the loss of water of crystallization, becoming anhydrous -> NaSO4.10H2O increases solubility when t < 32.5oC, above this t solubility decreases because NaSO4.10H2O dissolution is endothermic, NaSO4 is exothermic.

28. 3. pH Factor

• pH affects solubility related to ionization:

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

• Weak bases: Alkaloids, Chlorpromazine, etc. -> pH increases, solubility decreases.

• Amphoteric substances: Amino acids, Oxytetra, etc.

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

• Note: Stability of the active ingredient: Chloramphenicol.

29. 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.

• Crystalline forms with a stable structure are usually less soluble than amorphous forms: Novobiocin has an amorphous form that is 10 times more soluble than the crystalline form.

30. 5. Presence of Other Substances

• Electrolytes decrease the solubility of substances.

• -> Electrolytes should be diluted when combined with poorly soluble substances in solution.

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

31. 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 the medicinal substance in contact with the solvent.

• Cs: Saturation concentration of the medicinal substance.

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

• h: Thickness of the diffusion layer.

32. Factors Affecting Dissolution Rate

1. Surface area of contact.

2. Temperature and viscosity of the medium.

3. Stirring.

4. Solubility of the solute.

33. 1. Surface Area of Contact of the Solute with the Solvent

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

34. 2. Temperature and Viscosity of the Medium

• For most substances, increased t increases dissolution rate:

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

• Due to decreased viscosity of the solvent -> V increases.

35. 3. Stirring

• Disrupt the diffusion layers, bring fresh solvent to the surface of the solute -> Increase the concentration difference, the thickness of the diffusion layer becomes very small -> Increase dissolution rate.

• Dissolving colloids: Let colloids absorb water, swell fully, avoid stirring -> Reduce the contact area.

36. Dissolution by Circulation (Per Descensum Method)

• The medicinal substance is sprinkled onto the surface of the solvent or placed in a cloth bag suspended in the solvent.

• The medicinal substance dissolves and forms a saturated solution layer.

• This layer has a higher density, sinks to the bottom of the vessel, pushing the new solvent layer with a lower density to the surface, continuing the dissolution.

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

37. 4. Solubility of the Solute

• Increased solubility -> Increased Cs -> Increased V.

38. Special Dissolution Methods

1. Formation of easily soluble derivatives.

2. Use of hydrophilic intermediates.

3. Use of a mixture of solvents.

4. Dissolution using surfactants.

39. 1. Forming 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.

• Typical example: Lugol’s solution: KI reacts with I2 (a very poorly soluble substance in water) to form the KI3 derivative (very soluble in water). The higher the KI concentration, the faster the reaction rate.

40. 2. Using Hydrophilic Intermediates

• Principle: Hydrophilic intermediates act as intermediaries linking the solvent and the solute.

• Molecules with many polar groups such as: -COOH, -OH, NH2, sulfate, etc., the rest is a straight or cyclic hydrocarbon radical.

• The organic part has an affinity for the hydrophobic part of the poorly soluble substance, the hydrophilic function has an affinity for water molecules -> Electrostatic interactions -> Increased solubility.

• Used in large proportions (sometimes larger than the amount of substance to be dissolved) -> Disadvantage in treatment.

41. Examples of using hydrophilic intermediates

• Sodium benzoate to dissolve Caffeine, Anesthesin.

• Citric acid to dissolve Calcium Glycerophosphate.

• Antipyrine or Uretan to increase the solubility of Quinine.

42. 3. Using a Mixture of Solvents

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

• Commonly used polar solvents: Ethanol, isopropanol, glycerin, propylene glycol, amines like ethylenediamine, etc.

• Water-alcohol mixtures -> dissolve camphor. Glycerin-alcohol-water mixtures dissolve alkaloids.

43. Examples of using a mixture of solvents

• Bromoform solution contains Bromoform – Glycerin – Ethanol in a ratio of 1:3:6.

44. 4. Using Surfactants (Surface Active Agents)

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

• Structure consists of two parts: hydrophilic and hydrophobic parts.

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

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

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

• Unpleasant taste (oral medications, should not use more than 3%), reduces the effectiveness of some medicinal substances.

45. Critical Micelle Concentration

• The concentration at which surfactant molecules aggregate into micelles (aggregations) and the solution becomes a colloidal solution.

46. Degradation and Stabilization of Pharmaceutical Solutions

• Causes: During preparation, medicinal substances undergo physical and chemical influences, leaving them in a thermodynamically unstable state. Medicinal substances in solution are in a molecularly dispersed state, making reactions very easy. Complete elimination of decomposition is difficult.

• Classification of changes:

1. Physical changes.

2. Chemical changes.

3. Biological changes (microbial contamination).

47. 1. Physical Changes

• Includes the following phenomena:

• Precipitation.

• Coagulation of colloids.

• Color change or discoloration.

48. – Precipitation

• Concentrated solution with easily evaporating solvents.

• Precipitation due to salt formation occurs when easily soluble substances are added to solutions of poorly soluble substances.

• Ion exchange reactions produce poorly soluble substances when the medium changes, impurities release from the packaging, etc.

49. – Coagulation of Colloids

• Depends on the nature and concentration of the colloid.

• The presence of promoting agents such as electrolytes, pH, etc.

• Aging phenomenon of colloids in alcoholic preparations, liquid extracts, etc.

• Causes changes in viscosity, color.

50. – Color Change or Discoloration

• Chemical changes cause discoloration or color formation.

• Creates an impression of instability in the preparation.

51. 2. Chemical Changes

• Change the sensory and physical properties.

• Reduce or eliminate the therapeutic efficacy of the preparation.

• Produce degradation products that are toxic or have side effects.

• Includes:

• Oxidation-reduction reactions.

• Hydrolysis reactions.

• Racemization reactions.

• Complex formation reactions.

52. – Oxidation-Reduction Reactions

• An electron exchange reaction between two substances, one substance is oxidized, one substance is reduced.

• Conditions:

• Presence of oxygen.

• Presence of catalysts.

• Temperature.

• Light.

• Measures to limit:

• Use antioxidants.

• Store in sealed containers, away from light, high temperatures.

• Use appropriate packaging.

53. – Hydrolysis Reactions

• Decomposition reaction of organic compounds in water.

• Conditions:

• Presence of water.

• Temperature.

• pH.

• Measures to limit:

• Use anhydrous solvents.

• Adjust pH.

• Store in a dry, cool place.

54. – Racemization Reactions

• Conversion of an enantiomer to its opposite enantiomer.

• Conditions:

• Temperature.

• pH.

• Heavy metals.

• Measures to limit:

• Use pure raw materials.

• Adjust pH.

• Store in a cool place, avoid contact with heavy metals.

55. – Complex Formation Reactions

• A reaction to form a new complex from two or more substances.

• Conditions:

• Presence of heavy metal ions.

• pH.

• Measures to limit:

• Use purified water, free of heavy metal ions.

• Adjust pH.

56. 3. Biological Changes (Microbial Contamination)

• Microorganisms can grow in solution, causing spoilage and degradation of the medicinal substance.

• Measures to limit:

• Use purified water or deionized water.

• Use preservatives.

• Store in a clean, cool place.

• Package in sealed containers, avoid contact with air.

57. Notes:

• Preparing pharmaceutical solutions should comply with the regulations of the Vietnamese Pharmacopeia and food safety regulations.

• Use raw materials and excipients of clear origin and guaranteed quality.

• Pay attention to factors affecting the solubility, dissolution rate, and stability of the medicinal substance in solution.

• Store pharmaceutical solutions properly to ensure therapeutic efficacy and safety for users.

58. References:

• Vietnamese Pharmacopeia.

• Pharmaceutical preparation materials.

• Reputable websites on health and pharmaceuticals.

59. Note:

• This article is for informational purposes only, it does not replace professional advice from a doctor or pharmacist.

• Read the instructions carefully before using any medication.

I hope this article has provided you with useful information about pharmaceutical solution preparation.