Pharmaceutics by ma2xa


									     Taibah University
 College of Health Sciences
   Department of Pharmacy

Pharmaceutics II
        PHR 206

College of Health Sciences
         2009 – 2010


                                                  Table of Contents





         Class 1: Simple mixtures containing soluble substances only .......................................... 4




         Class 5: Mixtures containing slightly-soluble liquids or solids ........................................ 7












Chapter 1                               Mixtures

                                  1. MIXTURES

   • Definition:

      Liquid medicine for internal use of which several doses are contained in
      one bottle.

   • Advantages:

      1. They are more quickly effective than, for example, tablets,
            which require previous disintegration-in the body before absorption
            can begin.
      2. Certain substances can only be given in liquid form, the character
            of the remedy, or the large dose, makes administration in any
            other from inconvenient, e. g. castor oil, liquid paraffin,
            ammonium acetate solution.
      3. The usefulness of some substances is largely dependent upon
            administration in a diffused form. For example, light kaolin is used
            to adsorb toxic substances in the gut, the great surface area of the fine
            powder giving Maximum adsorbent effect.
      4. Certain chemical substances, e. g. potassium iodide and potassium
            bromide, may cause pain if taken in the dry state as a powder or

   • Containers for mixtures:

    o Plain white bottles should be used for preference. The bottle selected
       should then be fitted with a cork. This fitting should be done before
       the medicine is put into the bottle, so that unsuitable corks may be
       returned to stock for later use. The ideal fit should leave about two -
       thirds of the cork projecting from the neck of the bottle, to ensure easy
       removal. A white label indicating the dose is affixed on the bottle.

Chapter 1                                Mixtures

   • Classification:

       Class 1. Simple mixtures containing soluble substances only.
       Class 2. Mixtures containing diffusible solids.
       Class 3. Mixtures containing indiffusible solids.
       Class 4. Mixtures containing precipitate forming liquids.
       Class 5. Mixtures containing slightly soluble liquids or solids.
       Class 6. Effervescent mixtures.
       Class 7. Miscellaneous mixtures.

Class 1: Simple mixtures containing soluble substances only

            Mixtures containing soluble substances such as sodium citrate,
            potassium citrate, magnesium sulphate, sodium sulphate and
            ephedrine hydrochloride are prepared by dissolving the solid in a
            portion of the vehicle which may be water or aromatic water as
            chloroform water or an infusion as infusion of senege or a decoction
            as decoction of ammi visnaga and straining the prepared solution.
            The other liquid ingredients (spirit, syrup, tincture, extract) are then
            added and the mixture completed with the vehicle to volume.

Class 2: Mixtures containing diffusible solids

            Diffusible solids are those which do not dissolve in water, but may be
            mixed therewith so that, upon shaking, the powder is evenly diffused
            throughout the liquid for sufficient time to ensure uniform
            distribution in each dose.

            Examples of diffusible solids include: Rhubarb powder, aromatic
            chalk powder, compound rhubarb powder, bismuth subnitrate
            compound bismuth powder, compound kaolin powder,, compound
            liquorice powder, compound magnesium trisilicate powder, light kaolin,
            light and heavy magnesium oxide, light and heavy magnesium
Chapter 1                                 Mixtures

            trisilicate, phenolphthalein, quinine sulphate, and compound jalap
            powder are diffusible insoluble .

            Diffusible substance when introduced into mixtures requires no
            suspending agents.

            The presence of air in the interstices of many powders, particularly those
            of vegetable origin, causes some of the powder to float on the water. To
            prevent this tendency, make a smooth cream first, by adding only a small
            quantity of vehicle, and then-diluting.

Class 3: Mixtures containing indiffusible solids

            A solid is regarded as indiffusible when it will not remain evenly
            distributed in the vehicle long enough to ensure uniformly of the
            measured dose.

            The vehicle must, therefore, be increased in viscosity, and it should be
            noticed that the viscosity required to hold a given powder in suspension
            for a stated period is independent of the quantity of the powder. Therefore,
            the amount of suspending agent required depends upon the volume of the

            Examples of insoluble indiffusible solids include: Acetylsalicylic acid
            (aspirin) benzoic acid, bismuth oxychloride, bismuth salicylate, calomel,
            chlorbutol, phenacetin, phenobarbitone, prepared chalk, quinidine
            sulphate, Quinine salicylate, Salicylic acid, salol, succinylsulphathiazole,
            sulphadimidine, acetanilide, and resins of guaiacum, Jalap, podophyllum
            and scammony. All of these solids require a suspending agent when
            prescribed in mixtures

            Suspending agents:

Chapter 1                                 Mixtures

               There are many suspending agents which can be used. The best
               suspending agents for general use are:

               1. Compound powder of tragacanth: 2% w/v
               2. Powder of tragacanth: 6.25% to 6.32% w/v
               3. Powder of acacia 6% to 10% w/v
               4. Mucilage of tragacanth; 1/4 the volume of the mixture.
               5. Mucilage of acacia: 1/4 the volume of the mixture.

               For bismuth salts in mixtures, the suspending agents that can be used
               are compound powder of tragacanth, powder of tragacanth and
               mucilage of tragacanth, but not powder of acacia or mucilage of
               acacia because they tend to form Cement - like mass at the bottom of
               the bottle.

Class 4: Mixtures containing precipitate forming liquids

            Certain liquid preparations contain resinous matter, when mixed with
            water, the resin is precipitated and may adhere to the sides of the bottle,
            or form a clotted precipitates which will not rediffuse upon shaking. This
            happens particularly when salts are present.

            Resins of scammony, podophyllum, jalap, guaiacum are insoluble and
            form indiffusible masses, particularly when salts are present. Resinous
            tinctures and extracts as ammoniated tinctures of guaiacum, and of
            quinine, compound tincture of benzoin, liquid extract of hydrastis,
            tinctures of asafetida, of tolu and of podophyllum when mixed with water,
            the resin is precipitated and may adhere to the bottle to form a clotted
            precipitate, which will not rediffuse upon shaking.

            A suspending agent must be added such as compound powder of
            tragacanth ( 2% w/v) or mucilage of tragacanth (25% w/v).

Chapter 1                                Mixtures

            Tinctures of cubebs, of jalap and of myrrh when added to water,
            their resins precipitated in a diffusible state, and thus they do not
            need a suspending agent except when salts are present in
            appreciable proportions.

            If the mixture contains other tinctures or spirits, they are mixed
            with the resinous tinctures first before adding to water or to the
            vehicle. The suspending agent is added before adding the precipitate
            forming liquids.

Class 5: Mixtures containing slightly-soluble liquids or solids

 1. Slightly soluble liquids
            The insoluble portion of slightly soluble liquids is not readily
            diffusible, and a suspending agent is therefore necessary.
            Compound tragacanth powder (2% w/v) and tragacanth mucilage
            (25% v/v) are used for this purpose.

            Examples:          Creosote is soluble (1 in 150), guaiacol (1 in 80),
            paraldehyde (1 in 9), and amyl nitrite (almost insoluble). Alcohol,
            alcoholic tinctures, spirits and extracts facilitate their solution if
            present in favorable proportions.

 2. Slightly soluble solids:
            The insoluble portion of slightly soluble solids is diffusible and if
            presented in the form of a fine powder, it requires no suspending
            Examples of substances commonly prescribed in a quantity greater
            than will dissolve: Borax (1 in 20) boric acid (1 in 20), caffeine
            citrate (1 in 32) calcium lactate (1 in 20) and potassium chlorate (1
            in 14).

Chapter 1                               Mixtures

Class 6: Effervescent mixtures

            An effervescent mixture is one containing a recently prepared salt
            by combining an acid (citric, tartaric) and a bicarbonates or
            carbonate ( K, Na or NH4 ) at the time of dispensing and
            producing by this means a mixture charged with carbon dioxide.

            The substance that produces the effervescence may be added last
            without powdering.

            Effervescent preparations are more agreeable to the taste when
            slightly acid, and thus it is better to arrange for a slight excess of the

            1.Limonade purgative E.P. (Magnesium citrate).

             2. Effervescent mixture.

     Effervescent mixture E.P.

               Solution no. 1

               Sodium bicarbonate         40 g
               Simple syrup              170 ml
               Distilled water to       1000 ml

               Solution no. 2

               Citric acid                33 g
               Simple syrup              170 ml
               Spirit of lemon            10 ml
               Distilled water to       1000 ml
Chapter 1                               Mixtures

            • The two solutions are freshly prepared in separate bottles.

Class 7: Miscellaneous mixtures

1. Mixtures containing small doses of potent medicaments:
Substances like hyoscine hydrodromide, arsenic trioxide and "strychnine
hydrochloride require great care in dispensing the volume to be used.

2. Use of official solutions to obtain small doses:
The pharmacopoeia includes few solutions of potent substances, e.g. Arsenical
solution, containing 1% w/v of arsenic trioxide, adrenaline solution containing
0.1 % w/v of adrenaline, and morphine hydrochloride solution, containing, ,1%
w/v of morphine hydrochloride. These are convenient unsuitable cases where
fractions of a mg. are required.

3. Calcium lactate mixtures:
Samples of calcium lactate differ in the extent of solubility. This causes a
variation in the appearance of a mixture; sometimes it may be clear and
sometimes there may be a diffused powder. Some commercial specimens have
the objectionable odour of sour milk to an undesirable extent. When freshly
made, this odour is not so apparent, and solubility is also good. Calcium
carbonate and lactic acid are allowed to interact and boiled together for about
20 minutes in order to hydrolyze any lactide present in lactic acid to form lactic
acid which will react with calcium carbonate.

Chapter 1                                Mixtures

4. Other forms of mixtures:

      o A draught is a liquid medicine which is usually ordered in from one to
            three doses sent in a separate bottle.
      o Linctuses are viscous preparations usually containing medicaments
            having a local action on the mucous membrane of the throat and are
            usually prescribed for the relief of cough.
      o The vehicle is some mucilaginous syrupy or viscous substance. They
            are sipped or swallowed slowly without dilution in orders that they
            may have a prolonged action.
      o It usually consists of a simple solution of the active agent in a high
            concentration of sucrose often with other sweetening agents.
      o This type of products, which is also designed to be administered in
            multiples of 5 ml should be sipped slowly and do not diluted
      o The syrup content has a demulcent action on the mucous membranes
            of the throat.
      o For diabetic use the sucrose is usually replaced by sorbitol and /or
            synthetic sweeteners.
      o Examples are Codeine Linctus in sucrose syrup PC (11 th ed) &
            Diabetic Codeine Linctus in sorbitol solution, PC (11 th ed).

      o Elixirs are clear, pleasantly flavored, sweetened hydroalcoholic
            liquids intended for oral use.
      o The main ingredients in elixirs are ethanol and water but glycerin,
            sorbitol propylene glycol, flavoring agent, preservatives, and syrups

Chapter 1                                Mixtures

            often are used in the preparation of the final product. The solvents are
            often used to increase the solubility of the drug substance in the
            dosage form.
      o Elixirs are more fluid than syrups, due to the use of less viscous
            ingredients such as alcohol and the minimal use of viscosity-
            improving agents such as sucrose.
      o They are used as flavors and vehicles for drug substances (e.g.
            aromatic elixir USP).
      o Examples of medicated elixirs:
                 Dexamethasone elixir USP
                 Phenobarbital elixir USP
      o Occasionally, certain adverse effects (e.g., mucosal erosions) may be
            eliminated or reduced if the active drug (e.g. potassium chloride) is
            administered in elixir rather than in a solid dosage form.
      o The distinction between some of the medicated syrups and elixirs is
            not always clear however elixir must contain alcohol.
      o Elixirs also may contain glycerin and syrup. These may be added to
            increase the solubility of the medicinal agent, for sweetening purposes
            or to decrease the pharmacological effects of the alcohol. Some elixirs
            contain propylene glycol. Claims have been made for this solvent as a
            satisfactory substitute for both glycerin and alcohol.
      o An elixir may contain both water- and alcohol-soluble ingredients. If
            such is the case, the following procedure is indicated:
                 Dissolve the water-soluble ingredients in part of the water.
                 Add and solubilize the sucrose in the aqueous solution.
                 Prepare alcoholic solution containing the other ingredients.
                 Add the aqueous phase to the alcoholic solution, filter, and make
                 to volume with water.

Chapter 1                                Mixtures

                       Sucrose increases viscosity and decreases the solubilizing
                      properties of water and so must be added after primary
                      solution has been affected.
                       A high alcoholic content is maintained during preparation by
                      adding the aqueous phase to the alcoholic solution.
      o Elixirs that contain therapeutically active compounds are known as
            medicated elixirs. Phenobarbital elixir is considered a medicated

                  Phenobarbital                 4.00 g
                  Orange oil                    0.75 ml
                  Amaranth solution         10.00 ml
                  Alcohol                  150.00 ml
                  Glycerin                 450.00 ml
                  Syrup                    150.00 ml
                  Purified water, q.s.          1000.00 ml
                  Sig.: Phenobarbital elixir.

                       In preparing Phenobarbital elixir, the Phenobarbital and the
                       orange oil are dissolved in alcohol.
                        The remaining ingredients are then added, and the solution
                       is adjusted to final volume by the addition of water.
                       If all the ingredients were mixed and the Phenobarbital was
                       added last, the Phenobarbital would dissolve with difficulty.
                        The 15% alcohol in the Phenobarbital elixir is not sufficient
                       to maintain the Phenobarbital in solution. It is the aqueous

Chapter 1                               Mixtures

                     alcohol and glycerin solution that maintains the drug in
                     The addition of aqueous solutions to Phenobarbital elixir
                     may cause precipitation of the Phenobarbital.
      o Incompatibilities:
                  Because elixirs contain alcohol, incompatibilities of this solvent
                  are an important consideration during formulation.
                  Alcohol precipitates tragacanth, acacia, and agar from aqueous
                   If an aqueous solution is added to an elixir, a partial
                  precipitation of alcohol soluble ingredients may occur. This is
                  due to reduced alcoholic content of the final preparation.

   d. DROPS
      o A mixture is designated “Drops” when it is ordered in doses of less
            than one teaspoonful. Drops may be remedies given in their original
            form without dilution. Sometimes the remedy decomposes in aqueous
            media. Tincture of strophanthus contains the active principle
            strophanthin, a glycoside which is readily hydrolyzed by water to
            Strophanthidin which is inactive. To avoid this, it is prescribed
            generally in an alcoholic medium sometimes with compound tincture
            of cardamom.
      o Care must be taken to note the considerable difference between drops
            and minims. The weight of the minim of water is always constant
            while the weight of drop is variable with different substances. One
            minim approximately gives three drops of alcohol, five drops of
            chloroform, two and a half drops of tincture of belladonna, tincture of
            digitalis and tincture of opium.

Chapter 1                             Mixtures

      o Drops are usually sent out in bottles, accompanied by a standard
            dropper or a measure graduated in minims.

   • Protective effect of gums on colloidal precipitates:

   o The addition of an electrolyte, e.g. potassium bromide, and magnesium
      sulphate to certain colloidal solutions (e.g. resins) cause rapid
      agglomeration of the particles, with the formation of large visible
      particles, the colloid is then said to be precipitated. With other colloidal
      solutions, e.g. a solution of acacia or tragacanth no such precipitation
      takes place.
   o A solution of acacia is a protective colloid, i.e. not only is it stable with
      but it also prevents precipitation of other colloids when an electrolyte is
      added thereto.
   o The protective effect maybe explained by saying that the colloidal
      particles of acacia surround the particles of the other colloid, forming an
      effective barrier against the electrolyte.

   • Stock solutions:

   o It is quicker to measure a liquid than to weigh a solid, hence stable
      soluble salts in frequent use are often made into solutions of known
   o A common strength for very soluble substances is 1 in 3, meaning that 1
      gram contained in 3 milliliters of solution. Less soluble substances are
      necessarily stocked in weaker solutions, e.g. 1 in 6 or 1 in 8.
   o It must be remembered, however, that measuring is less accurate than
      weighing and great care must be taken to ensure a satisfactory degree of

Chapter 1                          Mixtures

   • Stock mixtures:

   o These are mixtures prepared in bulk, to enable small volumes to be
      dispensed quickly when required.

Chapter 1                             Mixtures

   • Suspending Agents

The following materials are those most widely used for the modification of
suspension viscosity.

    o Polysaccharides

      1. Acacia

            Acacia This natural material is often used as a suspending agent
            for extemporaneously prepared suspensions.
            Acacia is not a good thickening agent and its value as a
            suspending agent is largely due to its action as a protective
            colloid. It is therefore useful for preparations containing
            tinctures of resinous materials that precipitate on addition to
            It is essential to ensure that any precipitated resin is well coated
            by the protective colloid before any electrolyte (which should be
            well diluted) is added.
            Acacia is not very effective for dense powders, and for these it
            is often combined with other thickeners such as tragacanth,
            starch and sucrose in compound tragacanth powder.
            Unfortunately, acacia mucilage becomes acidic on storage as a
            result of enzyme activity, and it also contains an oxidase
            enzyme which may cause deterioration of active agents that are
            susceptible to oxidation. This enzyme can, however, be
            inactivated by heat.
            Because of the stickiness of acacia it is rarely used in
            preparations for external use.

Chapter 1                            Mixtures

      2. Tragacanth
            Tragacanth This product will form viscous aqueous solutions.
            Its thixotropic and pseudoplastic properties make it a better
            thickening agent than acacia and it can be used both for internal
            and external products.
            Like acacia it is mainly used for the extemporaneous
            preparation of suspensions with a short shelf-life.
            Tragacanth is stable over a pH range of 4-7.5 but takes several
            days to hydrate fully after dispersion in water. The maximum
            viscosity of its dispersions is not, therefore, achieved until after
            this time, and can also be affected by heating.
            There are several grades of this material and only the best
            quality is suitable for use as a pharmaceutical suspending agent.
      3. Alginates
            Alginic acid, a polymer of D-mannuronic acid, is prepared
            from kelp, and its salts have suspending properties similar to
            those of tragacanth.
            Alginate mucilages must not be heated above 60°C as
            depolymerization occurs, with a consequent loss in viscosity.
            They are most viscous immediately after preparation, after
            which there is a fall to a fairly constant value after about 24
            Alginates exhibit a maximum viscosity over a pH range of 5-9,
            and at low pH the acid is precipitated.
            Sodium alginate (Manucol) is the most widely used material in
            this class but it is, of course, anionic and will be incompatible
            with cationic materials and with heavy metals. The addition of
            calcium chloride to sodium alginate dispersion will produce

Chapter 1                             Mixtures

             calcium alginate, which has a much higher viscosity. Several
             different viscosity grades are commercially available.
      4. Starch
             Starch is rarely used on its own as a suspending agent but is one of
             the constituents of compound tragacanth powder, and it can also be
             used with carmellose sodium.
             Sodium starch glycolate (Explotab, Primojel), a derivative of
             potato starch, has also been evaluated for its use in the
             extemporaneous preparation of suspensions.
      5. Xanthan gum (keltrol)
             This is an anionic heteropolysaccharide produced by the action of
             Xanthomonas campestris on corn sugars. It is very soluble in cold
             water and is one of the most widely used thickening agents for the
             extemporaneous preparation of suspensions for oral use.
             It is used in concentrations up to about 2% and is stable over a
             wide pH range.

    o Water-soluble celluloses

            Several cellulose derivatives are available that will disperse in water
            to produce viscous colloidal solutions suitable for use as suspending

      1. Methylcellulose (Celacol, Methocel)
             This is a semisynthetic polysaccharide of the general formula:

             and is produced by the methylation of cellulose.
             Several grades are available, depending on their degree of
             methylation and on the chain length. The longer the chain, the
             more viscous is its solution. For example, a 2% solution of

Chapter 1                             Mixtures

            methylcellulose 20 exhibits an apparent viscosity of 20 millipascal
            seconds (mPa s) and methylcellulose 4500 has value of 4500 mPa
            s at 2% concentration.
            Because these products are more soluble in cold water than in hot,
            they are often dispersed in warm water and then, on cooling with
            constant stirring, a clear or opalescent viscous solution is
            Methylcelluloses are non-ionic and therefore stable over a pH
            range of 3-11, and are compatible with many ionic additives.
            When these dispersions are heated, the methylcellulose molecules
            become progressively dehydrated and eventually gel at about
            50°C; on cooling the original form is regained.

      2. Hydroxyethylcellulose (Natrosol)
            This compound has hydroxyethyl instead of methyl groups
            attached to the cellulose chain and is also available in different
            viscosity grades. It has the advantage of being soluble in both hot
            and cold water and will not gel on heating. Otherwise it exhibits
            the same properties as methylcellulose.

      3. Carmellose sodium (sodium carboxymethylcellulose)
            This material can be represented by:

            where x represents the degree of substitution, usually about 0.7,
            which in turn affects its solubility.
            The viscosity of its solution depends on the value of n, which
            represents the degree of polymerization. The numerical suffix
            gives an indication of the viscosity of a 2% solution. For example
Chapter 1                             Mixtures

            sodium carboxymethylcellulose 50 at a concentration of 2% will
            have a viscosity of 50 mPa s.
            This material produces clear solutions in both hot and cold water,
            which are stable over a pH range of about 5-10.
            Being anionic, this material is incompatible with polyvalent
            cations and the acid will be precipitated at low pHs. Heat
            sterilization of either the powder or its mucilage will reduce the
            viscosity, and this must be taken into account during formulation.
            It is widely used at concentrations of up to 1 % in products for
            oral, parenteral or external use.

      4. Microcrystalline cellulose
            This material consists of crystals of colloidal dimensions which
            disperse readily in water (but are not soluble) to produce
            thixotropic gels.
            It is a widely used suspending agent and the rheological properties
            of its dispersions can often be improved by the incorporation of
            additional hydrocolloid, in particular carboxymethylcellulose,
            methylcellulose and hydroxypropylmethylcellulose. These will aid
            dispersion and also stabilize the product against the flocculating
            effects of added electrolyte.

    o Hydrated silicates

            There are three important materials within this classification,
            namely bentonite, magnesium aluminium silicate and hectorite,
            and they belong to a group called the montmorillonite clays.
            They hydrate readily, absorbing up to 12 times their weight of
            water, particularly at elevated temperatures. The gels formed are
            thixotropic and therefore have useful suspending properties.

Chapter 1                              Mixtures

            As with most naturally occurring materials they may be
            contaminated with spores, and this must be borne in mind when
            considering a sterilization process and choosing a preservative
      1. Bentonite
            This has the general formula:

            It is used at concentrations of up to 2 or 3% in preparations for
            external use, such as calamine lotion.
            As this product may contain pathogenic spores it should be
            sterilized before use.
      2. Magnesium aluminium silicate (Veegum)
            It is also known as attapulgite, this is available as insoluble flakes
            that disperse and swell readily in water by absorbing the aqueous
            phase into its crystal lattice.
            Several grades are available, differing in their particle size, their
            acid demand and the viscosity of their dispersions.
            They can be used both internally and externally at concentrations
            of up to about 5%, and are stable over a pH range of 3.5-11.
            Veegum/water dispersions will exhibit thixotropy and plasticity
            with a high yield value, but the presence of salts can alter these
            rheological properties because of the flocculating effect of their
            positively charged counter-ions. Some grades, however, have a
            higher resistance to flocculation than others.
            This material is often combined with organic thickening agents
            such as sodium carboxymethylcellulose or xanthan gum to
            improve yield values and degree of thixotropy, and to control

Chapter 1                             Mixtures

      3. Hectorite
             This material is similar to bentonite and can be used at
             concentrations of 1-2% for external use.
             It is also possible to obtain synthetic hectorites (Laponite) that do
             not exhibit the batch variability or level of microbial contamination
             associated with natural products, and which can also be used
             As with other clays it is often advantageous to include an organic
             gum to modify its rheological properties.

    o Carbomers (carboxypolymethylene)

            This material is a totally synthetic copolymer of acrylic acid and
            allyl sucrose.
            It is used at concentrations of up to 0.5%, mainly for external
            application, although some grades can be taken internally.
            When dispersed in water it forms acidic, low-viscosity solutions
            which, when adjusted to a pH of between 6 and 11, become highly

    o Colloidal silicon dioxide (Aerosil)

            When dispersed in water this finely divided product will aggregate,
            forming a three-dimensional network.
            It can be used at concentrations of up to 4% for external use, but has
            also been used for thickening non-aqueous suspensions.

Chapter 2                            Suspensions

                                  2. SUSPENSIONS

• Definition of suspension:

Suspensions are preparations that contain fine drug particles distributed
uniformly throughout a vehicle in which the drug exhibits minimum solubility.
A pharmaceutical suspension is usually a coarse dispersion in which insoluble
solid particles are dispersed in a liquid system. The particles usually have
diameter greater than 0.1 μm.

• Physical properties of well formulated suspensions

   o The product must remain sufficiently homogenous for at least the period
      between shaking the container and removing the required amount.
   o The sediment produced on storage, if any, must be easily re-suspended
      by moderate agitation of the container.
   o The product may be required to be thickened in order to reduce the rate
      of settling of the particles. The resulting viscosity must not be so high
      that removal of the product from the container and transfer to the site of
      application is difficult.
   o Any suspended particles should be small and uniformly sized in order to
      give a smooth, elegant product, free from a gritty texture.

• Theory of suspension

1. Surface free energy:

      For the formulation of suspensions work must be done to reduce a large
      solid material into small particles and disperse them in a continuous

Chapter 2                            Suspensions

      Particle size reduction may be achieved by; Milling, Micro-pulverization,
      Fluid energy grinding, jet milling or micronizing, spray drying.
      This comminution process results in the generation of surface free energy
      that makes the system thermodynamically unstable as the resultant small
      particles are highly energetic and tend to regroup in such a way as to
      decrease the total area and reduce the surface free energy.
      The particles in a liquid suspension therefore tend to form light, fluffy
      conglomerates known as floccules that are held together by weak van der
      Waals forces. Under certain conditions, the particle may adhere by
      stronger forces to form aggregates known as cakes.
      The formation of any type of aggregate, either floccules or cakes, is
      perceived as a measure of the system's tendency to reach a more
      thermodynamically stable state.
      An increase in the work, W, or surface free energy, ΔG, brought about by
      dividing the solid into smaller particles and eventually increasing the
      total surface area, ΔA, is given by:
                                  ΔG = γSL •ΔA
                Where γSL , is the interfacial tension between the liquid medium
                and the solid particles.
      In order to approach a stable state, the system tends to reduce the surface
      free energy. This may be achieved either by a reduction of interfacial
      tension or by a reduction of the interfacial area.
      Interfacial tension can be reduced by the addition of a surfactant.
      Reduction of interfacial area, on the other hand, is achieved through
      formation of floccules or cakes.

Chapter 2                           Suspensions

2. Electrical properties:

2.1 Electric Double Layer
   o When dispersed particles are in contact with an aqueous solution of an
      electrolyte, the particles may selectively adsorb one charge species. If the
      adsorbed species is an anion, the particles will be overall negatively
   o The ions that give the particle its charge, anions in this case, are called
      potential-determining ions or co-ions.
   o Remaining ionic species in the solution are the rest of the anions and the
      total number of cations added. This means, there will be excess cations
      than anions in the dispersion medium.
   o These cations having a charge opposite to that of the potential-
      determining ions are known as counter-ions. They are attracted to the
      negatively charged surface by electric forces.
   o Counter-ions also repel the approach of any further anions to particle
      surface, once the initial adsorption is complete.
   o These electric forces and thermal motion keeps an equal distribution of
      all the ions in solution. It results in an equilibrium condition where some
      of the excess cations approach the surface and the rest of the cations will
      be distributed in decreasing the amounts as one moves away from the
      charged surface. This situation is explained in Fig. 2.1.
   o The part of the solvent immediately surrounding the particles will almost
      entirely comprise of the counter-ions. This part of the solvent, along with
      these counter-ions is tightly bound to the particle surface and is known as
      the Stern layer.
   o When particles move through the dispersion medium, the Stern layer
      moves along with them and thus the shear plane is the one peripheral to
      the Stern layer.

Chapter 2                              Suspensions

   o There are fewer counter-ions in the tightly bound layer than co-ions
      adsorbed onto the surface of the solid. Therefore, the potential at the
      shear plane is still negative.
   o Surrounding the Stern layer is the diffuse layer that contains more
      counter-ions than co-ions. The ions in this layer are relatively mobile
      and, because of thermal energy, they are in a constant state of motion into
      and from the main body of the continuous phase.
   o Electric neutrality occurs where the mobile diffuse layer ends. Beyond
      the diffuse layer, the concentrations of co- and counter-ions are equal,
      that is, conditions of electric neutrality prevail throughout the remaining
      part of the dispersion medium.

   o Thus, the electric distribution at the solid–liquid interface can be
      visualized as a double layer of charge. The Stern layer, the first layer is
      tightly bound to the solid surface and contains mostly the counter-ions.
      The second layer is more mobile containing more counter-ions than co-
      ions. These two layers are commonly known as the electric double layer.
   o The thickness of the double layer depends upon the type and
      concentration of ions in solution. It is important to note that the

Chapter 2                            Suspensions

      suspension, as a whole is electrically neutral despite the presence of
      unequal distribution of charges in the double layer.
   o Two other situations may arise. Should the concentration of counter-ions
      in the tightly bound layer be equal to that of the co-ions on the solid
      surface, then electric neutrality will occur at the shear plane and there
      will be only one layer of medium and ions, instead of double layer.
   o However, if the total charge of the counter-ions in the Stern layer exceeds
      the charge due to the co-ions, the net charge at the shear plane will be
      positive rather than negative. It means electric neutrality will be achieved
      where the electric double layer ends and the diffuse layer, will contain
      more co-ions than counter-ions.
   o The charge density at any distance from the surface is determined by
      taking the difference in concentration between positive and negative ions
      at that point.

2.2 Nernst and Zeta Potentials
   o The electric double layer is formed in order to neutralize the charged
      particles in a suspension.
   o As discussed before the electrical potential at any point in a suspension
      system depends on its exact location.
   o The potential in the diffuse layer gradually changes as one moves away
      from a solid particle. This is shown in Fig. 2.2.
   o The difference in electric potential between the actual or true surface of
      the particle and the electroneutral region is referred to as the surface or
      electrothermodynamic or Nernst potential (E).
   o Hence, Nernst potential is controlled by the electrical potential at the
      surface of the particle due to the potential determining ions.
   o The potential difference between the shear plane and the electroneutral
      region is known as the electrokinetic or zeta (z) potential (Fig. 2.3).

Chapter 2                            Suspensions

   o While Nernst potential has little influence in the formulation of stable
      suspension, zeta potential has significant effect on it.
   o Zeta potential governs the degree of repulsion between adjacent,
      similarly charged solid dispersed particles. If the zeta potential is reduced
      below a certain value, which depends on the specific system under
      investigation, the attractive forces between particles due to van der
      Waals’ force, overcome the forces of repulsion and the particles come
      together to form floccules. This phenomenon is known as flocculation.
   o The magnitude of surface and zeta potentials is related to the surface
      charge and the thickness of the double layer.

Chapter 2                              Suspensions

• Rationale for suspensions formulation

   o The reasons for preparing a suspension are:
      1. Certain drugs are chemically unstable in solution phase but stable in
            suspension. In this case, the suspension can assure the stability while
            delivering the drugs in liquid dosage form.
      2. Many patients prefer the liquid formulation over the solid form of the
            same drug since it is easier to swallow.
      3. The flexibility in administration of a range of doses for a liquid
            dosage form than a solid dosage form (as tablets) for infants, children,
            and the elderly.
      4. Suspension helps improve the taste of some poor-tasting drugs,
            because the dispersion medium can be sweetened and flavored.
      5. A suspension is often a suitable dosage form to be given orally, in
            dermatology (Topical or on the skin) and for the parenteral (IM, SC)
            administration of insoluble drugs.
      6. Many antibiotic agents are unstable in solution for a period of time;
            therefore, packaging as a dry powder to be reconstituted by adding the
            dispersion medium when filling the prescription is a good approach.
   o Common pharmaceutical suspensions belong to three groups: (1) Oral
      suspensions (syrups) which have the most common application of
      suspension, (2) external suspension (lotions), and (3) parenteral
   o The following are examples of some common oral suspensions:
       ♦       Alumina, magnesia, and simethicone oral suspension.
       ♦       Magnesia and alumina oral suspension.
       ♦       Sulfamethoxazole and trimethoprim oral suspension.
       ♦       Amoxicillin for oral suspension.
       ♦       Ampicillin for oral suspension.
       ♦       Cefixime for oral suspension.
Chapter 2                            Suspensions

   o The last three preparations consist of specific amounts of dry powder
      mixtures or granules, which are intended to be suspended in a specific
      quantity of water or some other vehicle prior to oral administration to
      produce a specific concentration.

• Formulation of Suspension

   1. Particle size control

   o It is first necessary to ensure that the drug to be suspended is of a fine
      particle size prior to formulation. This is to ensure a slow rate of
      sedimentation of the suspended particles.
   o Large particles, if greater than about 5 µm diameter, will also impart a
      gritty texture to the product, and may cause irritation if injected or
      instilled into the eyes.
   o The ease of administration of a parenteral suspension may depend upon
      particle size and shape, and it is quite possible to block a hypodermic
      needle with particles over about 25 µm diameter, particularly if they are
      acicular in shape rather than isodiametric.
   o A particular particle size range may also be chosen in order to control the
      rate of dissolution of the drug and hence its bioavailability.
   o Even though the particle size of a drug may be small when the
      suspension is first manufactured, there is always a degree of crystal
      growth that occurs on storage, particularly if temperature fluctuations
      occur. This is because the solubility of the drug may increase as the
      temperature rises, but on cooling, the drug will crystallize out. This is a
      particular problem with slightly soluble drugs such as paracetamol.
   o If the drug is polydispersed, then the very small crystals of less than 1 µm
      diameter will exhibit a greater solubility than the larger ones.
   o Over a period of time the small crystals will become even smaller,
      whereas the diameters of the larger particles will increase.

Chapter 2                             Suspensions

   o It is therefore advantageous to use a suspended drug of a narrow size
      range. The inclusion of surface-active agents or polymeric colloids,
      which adsorb on to the surface of each particle, may also help to prevent
      crystal growth.
   o Different polymorphic forms of a drug may exhibit different solubilities,
      the metastable state being the most soluble. Conversion of the metastable
      form, in solution, to the less soluble stable state, and its subsequent
      precipitation, will lead to changes in particle size.

2. The use of wetting agents

   o Some insoluble solids may be easily wetted by water and will disperse
      readily throughout the aqueous phase with only minimal agitation.
   o Most, however, will exhibit varying degrees of hydrophobicity and will
      not be easily wetted. Some particles will form large porous clumps within
      the liquid, whereas others remain on the surface and become attached to
      the upper part of the container.
   o The foam produced on shaking will be slow to subside because of the
      stabilizing effect of the small particles at the liquid/air interface.
   o To ensure adequate wetting, the interfacial tension between the solid and
      the liquid must be reduced so that the adsorbed air is displaced from the
      solid surfaces by the liquid.
   o The particles will then disperse readily throughout the liquid, particularly
      if an intense shearing action is used during mixing.
   o If a series of suspensions is prepared, each containing one of a range of
      concentrations of wetting agent, then the concentration to choose will be
      the lowest that provides adequate wetting.
   o The following is a discussion of the most widely used wetting agents for
      pharmaceutical products.

Chapter 2                              Suspensions

   a. Surface-active agents
            Surfactants possessing an HLB value between about 7 and 9 would be
            suitable for use as wetting agents. The hydrocarbon chains would be
            adsorbed by the hydrophobic particle surfaces, whereas the polar
            groups project into the aqueous medium and become hydrated.
            Wetting of the solid occurs as a result of a fall both in interfacial
            tension between the solid and the liquid and, to a lesser extent,
            between the liquid and air.
            Most surfactants are used at concentrations of up to about 0.1 % as
            wetting agents and include, for oral use, the polysorbates (Tweens)
            and sorbitan esters (Spans). For external application, sodium lauryl
            sulphate, sodium dioctylsulphosuccinate and quillaia extract can also
            be used.
            The choice of surfactant for parenteral administration is obviously
            more limited, the main ones used being the polysorbates, some of the
            poloxamers (polyoxyethylene/polyoxypropylene copolymers) and
            Disadvantages in the use of this type of wetting agent include
            excessive foaming and the possible formation of a deflocculated
            system, which may not be required.

   b. Hydrophilic colloids
            These materials include acacia, bentonite, tragacanth, alginates,
            xanthan gum and cellulose derivatives, and will behave as protective
            colloids by coating the solid hydrophobic particles with a
            multimolecular layer.
            This will impart a hydrophilic character to the solid and so promote
            wetting. These materials are also used as suspending agents and may,
            like surfactants, produce a deflocculated system, particularly if used at
            low concentrations.
Chapter 2                               Suspensions

   c. Solvents
            Materials such as alcohol, glycerol and glycols, which are water
            miscible, will reduce the liquid/air interfacial tension.
            The solvent will penetrate the loose agglomerates of powder
            displacing the air from the pores of the individual particles, so
            enabling wetting to occur by the dispersion medium.

3. Flocculated and deflocculated systems

   o Having incorporated a suitable wetting agent, it is then necessary to
      determine whether the suspension is flocculated or deflocculated and to
      decide which state is preferable.
   o Whether or not a suspension is flocculated or deflocculated depends on
      the relative magnitudes of the forces of repulsion and attraction between
      the particles.
   o In a deflocculated system the dispersed particles remain as discrete units
      and, because the rate of sedimentation depends on the size of each unit,
      settling will be slow.
   o The supernatant of a deflocculated system will continue to remain cloudy
      for an appreciable time after shaking, due to the very slow settling rate of
      the smallest particles in the product, even after the larger ones have
   o The repulsive forces between individual particles allow them to slip past
      each other as they sediment. The slow rate of settling prevents the
      entrapment of liquid within the sediment, which thus becomes compacted
      and can be very difficult to redisperse.
   o This phenomenon is also called caking or claying, and is the most serious
      of all the physical stability problems encountered in suspension

Chapter 2                                     Suspensions

   o In a flocculated system, the aggregation of particles will lead to a much
       more rapid rate of sedimentation or subsidence because each unit is
       composed of many individual particles and is therefore larger.
   o The rate of settling will also depend on the porosity of the aggregate,
       because if it is porous the dispersion medium can flow through, as well as
       around, each aggregate or floccule as it sediments.
   o The nature of the sediment of a flocculated system is also quite different
       from that of a deflocculated one. The structure of each aggregate is
       retained after sedimentation, thus entrapping a large amount of the liquid
       phase. The volume of the final sediment will still be large and will easily
       be redispersed by moderate agitation.
   o In a flocculated system the supernatant quickly becomes clear, as the
       large flocs that settle rapidly are composed of particles of all sizes.

The sedimentation behaviour of flocculated and deflocculated suspensions. Within a few minutes of
manufacture (a) there is no apparent change within the deflocculated system compared to its initial
appearance. Even after several hours (b) there is still little obvious change, except that the
concentration of solids in the lower layers has increased at the expense of the upper layers owing to
slow particle sedimentation. There is a small amount of a compact sediment. After prolonged storage
(c), depending on the physical stability of the system, the supernatant has cleared, leaving a compact
sediment. In the flocculated system at (a) there is some clear supernatant with a distinct boundary
between it and the sediment. At (b) there is a larger volume of clear supernatant with a relatively large
volume of a porous sediment, which does not change further even after prolonged storage (c).

Chapter 2                              Suspensions

   o In summary, deflocculated systems have the advantage of a slow
      sedimentation rate, thereby enabling a uniform dose to be taken from the
      container, but when settling does occur the sediment is compacted and
      difficult to redisperse. Flocculated systems form loose sediments which
      are easily redispersible, but the sedimentation rate is fast and there is a
      danger of an inaccurate dose being administered; also, the product will
      look inelegant.

   a. Controlled flocculation
            A deflocculated system with a sufficiently high viscosity to prevent
            sedimentation would be an ideal formulation.
            It cannot be guaranteed, however, that the system would remain
            homogenous during the entire shelf-life of the product.
            Usually a compromise is reached in which the suspension is partially
            flocculated to enable easy redispersion if necessary, and viscosity is
            controlled so that the sedimentation rate is at a minimum.
            So the next stage of the formulation process, after the addition of the
            wetting agent, is to ensure that the product exhibits the correct degree
            of flocculation.
            Underflocculation will give those undesirable properties that are
            associated with deflocculated systems. An overflocculated product
            will look inelegant and, to minimize settling, the viscosity of the
            product may have to be so high that any necessary redispersion would
            be difficult.
            Controlled flocculation is usually achieved by a combination of
            particle size control, the use of electrolytes to control zeta potential,
            and the addition of polymers to enable crosslinking to occur between
            particles. Some polymers have the advantage of becoming ionized in

Chapter 2                              Suspensions

            an aqueous solution, and can therefore act both electrostatically and
            sterically. These materials are also termed polyelectrolytes.

   b. Flocculating agents
            In many cases, after the incorporation of a non-ionic wetting agent a
            suspension will be found to be deflocculated, either because of the
            reduction in solid/liquid interfacial tension, or because of the hydrated
            hydrophilic layer around each particle forming a mechanical barrier to
            The use of an ionic surfactant to wet the solid could produce either a
            flocculated or a deflocculated system, depending on any charge
            already present on the particles. If particles are of opposite charge to
            that of the surfactant then neutralization will occur. If a high charge
            density is imparted to the suspended particles then deflocculation will
            be the result.
            If it is necessary for the suspension to be converted from a
            deflocculated to a partially flocculated state, this may be achieved by
            the addition of electrolytes, surfactants and/or hydrophilic polymers.

 i. Electrolytes
            The addition of an inorganic electrolyte to an aqueous suspension will
            alter the zeta potential of the dispersed particles and, if this value is
            lowered sufficiently, flocculation may occur.
            The Schultz-Hardy rule shows that the ability of an electrolyte to
            flocculate hydrophobic particles depends on the valency of its
            Although they are more efficient, trivalent ions are less widely used
            than mono- or divalent electrolytes because they are generally more
            toxic. If hydrophilic polymers, which are usually negatively charged,

 Chapter 2                                 Suspensions

             are included in the formulation they may be precipitated by the
             presence of trivalent ions.
             The most widely used electrolytes include the sodium salts of
             acetates, phosphates and citrates, and the concentration chosen will be
             that which produces the desired degree of flocculation.
             Care must be taken not to add excessive electrolyte or charge reversal
             may occur on each particle, so forming, once again, a deflocculated
ii. Surfactants
             Ionic surface-active agents may also cause flocculation by
             neutralizing the charge on each particle.
             Non-ionic surfactants will, of course, have a negligible effect on the
             charge density of a particle but may, because of their linear
             configurations, adsorb on to more than one particle, thereby forming a
             loose flocculated structure.

iii. Polymeric flocculating agents
             Starch, alginates, cellulose derivatives, tragacanth, carbomers and
             silicates are examples of polymers that can be used to control
             Their linear branched-chain molecules form a gel-like network within
             the system and become adsorbed on to the surfaces of the dispersed
             particles, thus holding them in a flocculated state. Although some
             settling can occur, the sedimentation volume is large, and usually
             remains so for a considerable period.
             Care must be taken to ensure that, during manufacture, blending is not
             excessive as this may inhibit the crosslinking between adjacent
             particles and result in the adsorption of each molecule of polymer on
             to one particle only. If this should occur then a deflocculated system

Chapter 2                               Suspensions

            may result, because the formation of the hydrophilic barrier around
            each particle will inhibit aggregation. A high concentration of
            polymer may have a similar effect if the whole surface of each particle
            is coated.
            It is essential that areas on each suspended particle remain free from
            adsorbate, so that crosslinking can recur after the product is sheared.

   Table.1. Relative properties of flocculated and deflocculated suspensions
            Character               Deflocculated                Flocculated
                             Exist in suspension as       Form loose aggregates or
                             individual entities.         floccules.

   Rate of sedimentation     Slow                         high

                             Very closely packed and      loosely packed and easy to
                             the resulting hard cake is   redisperse
   The sediment
                             difficult, if not
                             impossible, to redisperse
                             after settling it remains    After rapid settling, a
                             cloudy.                      clear boundary exists
                                                          between the sediment and
                                                          the supernatant.

• Preparation of suspension

   o In the preparation of a suspension, the pharmacist must be familiar with
      the characteristics of both the dispersed phase and the dispersion
   o In some cases, the dispersed phase (powder) is readily wetted when
      added to the medium. However, sometimes the particles clump together
      and float on top of the vehicle and cause an uneven suspension. In these
      cases, the powder must be wetted firstly with wetting agent.
   o Examples of wetting agents used in case of aqueous vehicle as dispersion
      medium are alcohol, glycerol, propylene glycol or other hygroscopic

Chapter 2                            Suspensions

   o Once the powder is wetted, the dispersion medium is added and mixed
      thoroughly before addition of the vehicle.
   o The final product is then passed through a colloid mill or blender to
      insure uniformity. A preservative may be added to protect against
      bacterial contamination.

• Extemporaneous compounding of suspensions

   o Unfortunately, not all medicines are available in a convenient, easy-to-
      take liquid dosage form. Therefore, patients who are not able to swallow
      solid dosage medicines such as infants and elderly may present a special
   o Thus pharmacist may have to use a solid dosage form of the drug and
      extemporaneously compound a liquid product.
   o The contents of the capsule are to be putted into a mortar; if it is in tablet
      form, it will be crushed in a mortar with a pestle. Then the selected
      vehicle is slowly added to the powder and mixed well to create a paste
      before being diluted to the desired volume.
   o The difficulty that confronts the pharmacist is the stability of the drug
      when it is incorporated into a liquid vehicle. Drugs in liquid form have
      faster decomposition rates than those in solid form. To overcome this, the
      pharmacist can contact the pharmaceutical manufacturer to obtain
      stability information.

• Settling/Sedimentation in suspensions

   o Settling of the suspended particles leading to separation of dispersed
      particles and dispersion medium is the most important factor associated
      with the physical stability of a suspension.
   o Many factors involved in the rate of settling of the particles of a
      suspension are summarized in the equation of Stokes' law:

Chapter 2                             Suspensions

                               dx d ( ρ p − ρ m ) g

                               dt      18η

      dx/ dt is the sedimentation rate,
      d is the diameter of the particles,
      ρp is the density of particles,
      ρm is the density of medium,
      g is the gravitational constant, and
      η is the viscosity of the medium,

   o The equation is valid only in an ideal situation in which uniform,
      perfectly spherical particles settle in a very dilute suspension (i.e., no
      collision of the particles), without effecting turbulence in the medium and
      without chemical or physical attraction between the particles and the
   o While in practical cases, conditions are not in strict accord with the
      assumptions of Stokes' law, the above equation does give the factors that
      influence the rate of settling. It is apparent from the equation that rate of
      sedimentation (dx/dt) will be reduced by
      A. Decreasing the particle size (d), provided the particles are kept in a
            deflocculated state. This may be achieved by communition of the
            particles using appropriate techniques (pestle and mortar, colloid
            mills, etc.).,
      B. Minimizing the difference in densities between the particles and the
            dispersion medium (ρp- ρm). In fact control of settling by minimizing
            the difference in densities between the particles and the dispersion
            medium is not too practical.
      C. Increasing the viscosity of the dispersion medium (η). Viscosity of the
            dispersion medium can always be increased by the addition of

Chapter 2                              Suspensions

            viscosity    building    polymers        (methyl   cellulose,   carboxy
            methylcellulose, etc.). However, too high a viscosity is undesirable, as
            it may affect the redispersability and pourability of the suspension.


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