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Viscosity-enhancing agents The administration of oral solutions to patients is usually performed using a syringe, a small-metered cup or a traditional 5-ml spoon. The viscosity of the formulation must be sufficiently controlled in order to ensure the accurate measurement of the volume to be dispensed.

Furthermore, increasing the viscosity of some formulations may increase the palatability. Accordingly there is a viscosity range that the formulation should exhibit to facilitate this operation.

Certain liquid formulations do not require the specific addition of viscosity-enhancing agents, e. The viscosity of pharmaceutical solutions may be easily increased and controlled by the addition of non-ionic or ionic hydrophilic polymers.

Examples of both of these categories are shown below: Full details of the physicochemical properties of these polymers are provided in later chapters. Antioxidants Antioxidants are included in pharmaceutical solutions to enhance the stability of therapeutic agents that are susceptible to chemical degradation by oxidation.

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Typically antioxidants are molecules that are redox systems which exhibit higher oxidative potential than the therapeutic agent or, alternatively, are compounds that inhibit free radical-induced drug decomposition. Typically in aqueous solution antioxidants are oxidised and hence degraded in preference to the therapeutic agent, thereby protecting the drug from decomposition. Both water-soluble and water-insoluble antioxidants are commercially available, the choice of these being made according to the nature of the formulation.

Examples of antioxidants that may be used in oil-based solutions include: Antioxidants may also be employed in conjunction with chelating agents, e.

Preservatives Preservatives are included in pharmaceutical solutions to control the microbial bioburden of the formulation. Ideally, preservatives should exhibit the following properties: A wide range of preservatives is available for use in pharmaceutical solutions for oral use, including the following values in parentheses relate to the typical concentration range used in oral solutions: Usually a combination of two members of this series is employed in pharmaceutical solutions, typically methyl and propyl parahydroxybenzoates in a ratio of 9: The combination of these two preservatives enhances the antimicrobial spectrum.

Factors affecting preservative efficacy in oral solutions The activity of a preservative is dependent on the correct form of the preservative being available in the formulation at the required concentration to inhibit microbial growth termed the minimum inhibitory concentration: Unfortunately, in many solution formulations, the concentration of preservative within the formulation may be affected by the presence of other excipients and by formulation pH.

The pH of the formulation In some aqueous formulations the use of acidic preservatives, e. O 3HC OH OH a b The antimicrobial properties are due to the unionised form of the preservative; the degree of ionisation being a function of the pH of the formulation.

The activity of the unionised form of the acid in this respect is due to the ability of this form to diffuse across the outer membrane of the microorganism and eventually into the cytoplasm. The neutral conditions within the cytoplasm enable the preservative to dissociate, leading to acidification of the cytoplasm and inhibition of growth. The fraction of acidic preservative at a particular pH may be calculated using a derived form of the Henderson—Hasselbalch equation, as follows: Worked example Example 2.

The Henderson—Hasselbalch equation may be employed, as described above, to determine the fraction of unionised acid within the formulation. In practice an overage is added and therefore the actual concentration of preservative required would be 0. As the reader will observe, the pKa of the preservative is a vital determinant within the above calculations.

Organic acids, e. If the above calculation is repeated for an oral solution at pH 7. Importantly, the preservative efficacies of parabens alkyl esters of parahydroxybenozoic acid and the phenolics are generally not affected by formulation pH within a pH range between 4. The structures of these preservatives are shown in Figure 1.

OH The presence of micelles The role of micelles for the solubilisation of lipophilic therapeutic agents was described above. If the preservative exhibits lipophilic properties e.

An equilibrium is established, as depicted in Figure 1. The presence of hydrophilic polymers It has been shown that the free concentration of preservative in oral solution formulations is reduced in the presence of hydrophilic polymers, e. This is due to the ability of the preservative to interact chemically with the dissolved polymer.

As described above, this problem is addressed by increasing the concentration of preservative in the formulation. In certain circumstances the preservative may be incompatible with hydrophilic polymers in the formulation due to an electrostatic interaction. Therefore, cationic hydrophilic polymers should not be used in conjunction with acidic preservatives in oral solution formulations. Flavours and colourants Unfortunately the vast majority of drugs in solution are unpalatable and, therefore, the addition of flavours is often required to mask the taste of the drug substance.

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Taste-masking using flavours is a difficult task; however, there are some empirical approaches that may be taken to produce a palatable formulation. It has been proposed that certain flavours should be used to mask these specific taste sensations. In particular: Oral pharmaceutical solutions 15 — Flavours that may be used to mask a sweet taste include: In so doing these agents augment the taste-masking properties of conventional flavours. Colours are pharmaceutical ingredients that impart the preferred colour to the formulation.

Although the inclusion of colours is not a prerequisite for all pharmaceutical solutions, certain categories of solution e. Types of pharmaceutical solutions Tips The formulation of solutions for oral Pharmaceutical solutions for oral administration often requires the administration inclusion of several excipients.

There are three principal types of solution It is important that each excipient formulations that are administered orally: In necessary and justified. Details of agent. Oral solutions Oral solutions are administered to the gastrointestinal tract to provide systemic absorption of the therapeutic agent. Due to the resilience of the gastrointestinal environment, oral solutions may be formulated over a broad pH range.

However, unless there are issues regarding the solubility or stability of the therapeutic agent, the usual pH of oral solutions is circa 7. Typically the following classes of excipients are used in the formulation of oral solutions: For this purpose hydrophilic polymers are used, e.

The reader should note that, to be classified as a solution, all components of the formulation including the therapeutic agent should be soluble, with no evidence of precipitation. Oral syrups Syrups are highly concentrated, aqueous solutions of sugar or a sugar substitute that traditionally contain a flavouring agent, e. Therapeutic agents may either be directly incorporated into these systems or may be added as the syrup is being prepared.

If the former method is employed, it is important to ensure that the therapeutic agent is soluble within the syrup base. It should also be remembered that the choice of syrup vehicle must be performed with due consideration to the physicochemical properties of the therapeutic agent. For example, cherry syrup and orange syrup are acidic and therefore the solubility of acidic or some zwitterionic therapeutic agents may be lowered and may result in precipitation of the drug substance.

Under these circumstances, the physical stability of the preparation will have been compromised and the shelf-life of the product will have been exceeded. The use of acidic syrups may additionally result in reduced chemical stability for acid-labile therapeutic agents. The major components of syrups are as follows: Due to the inherent sweetness and moderately high viscosity of these systems, the addition of other sweetening agents and viscosity-modifying agents is not required.

In addition, the high concentration of sucrose and associated unavailability of water termed low water activity ensures that the addition of preservatives is not required. As the concentration of sucrose is reduced from the upper limit e. In some formulations, other non-sucrose bases may replace traditional syrup. These non-sucrose bases may be mixed with traditional syrups, if required, in the formulation of oral syrups that possess a low concentration of sucrose in comparison to traditional syrups.

For the afore-mentioned reasons, all medicinal products designed for administration to children and to diabetic patients must be sugar-free. Syrup substitutes must therefore provide an equivalent sweetness, viscosity and preservation to the original syrups. To achieve these properties artificial sweeteners typically saccharin sodium, aspartame , non-glycogenetic viscosity modifiers e.

As highlighted above, preservatives are not required in traditional syrups containing high concentrations of sucrose. Conversely, in sugar-free syrups, syrups in which sucrose has been substituted at least in part by polyhydric alcohol and in traditional syrups that contain lower concentrations of sucrose, the addition of preservatives is required.

Typical examples of commonly used preservatives include: The typical concentration range is 0. It is important to note that the preservative efficacy of these preservatives may be decreased in the presence of hydrophilic polymers generally employed to enhance viscosity , due to an interaction of the preservative with the polymer.

This effect is negated by increasing the overall preservative concentration. Other preservatives that are employed include benzoic acid 0. These are employed whenever the unpalatable taste of a therapeutic agent is apparent, even in the presence of the sweetening agents. The flavours may be of natural origin e.

Alternatively, a wide range of synthetic flavours are available that offer advantages over their natural counterparts in terms of purity, availability, stability and solubility. Certain flavours are also associated with a mild therapeutic activity. For example, many antacids contain mint due to the carminative properties of this ingredient. Alternatively other flavours offer a taste-masking effect by eliciting a mild local anaesthetic effect on the taste receptors.

Examples of flavours in this category include peppermint oil, chloroform and menthol. The concentration of flavour in oral syrups is that which is required to provide the required degree of taste-masking effectively. These are generally natural or synthetic water- soluble, photo-stable ingredients that are selected according to the flavour of the preparation.

For example, mint-flavoured formulations are commonly a green colour, whereas in banana-flavoured solutions a yellow colour is commonly employed. Such ingredients must not chemically or physically interact with the other components of the formulation. Oral elixirs An elixir is a clear, hydroalcoholic solution that is formulated for oral use. The concentration of alcohol required in the elixir is unique to each formulation and is sufficient to ensure that all of the other components within the formulation remain in solution.

For this purpose other polyol co-solvents may be incorporated into the formulation. The presence of alcohol in elixirs presents a possible problem in paediatric formulations and, indeed, for those adults who wish to avoid alcohol.

The typical components of an elixir are as follows: This is employed as a co-solvent to ensure solubility of all ingredients. As highlighted above, the concentration of alcohol varies depending on the formulation.

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Polyol co-solvents, e. The reader is directed to the pharmacopoeial monographs to observe the concentration of co-solvents in specific examples of the pharmaceutical elixirs. Table 1.

The concentration of sucrose in elixirs is less than that in syrups and accordingly elixirs require the addition of sweetening agents. The types of sweetening agents used are similar to those used in syrups, namely syrup, sorbitol solution and artificial sweeteners such as saccharin sodium Figure 1. It should be noted, however, that the high concentration of alcohol prohibits the incorporation of high concentrations of sucrose due to the limited solubility of this sweetening agent in the elixir vehicle.

O O S NNa 2H2O O sodium, an agent which is used in small quantities and which exhibits the required solubility profile in the elixir, is employed. All pharmaceutical elixirs contain flavours and colours to increase the palatability and enhance the aesthetic qualities of the formulation. The presence of alcohol in the formulation allows the pharmaceutical scientist to use flavours and colours that may perhaps exhibit inappropriate solubility in aqueous solution.

For example, it may be observed that in the two formulations cited above, essential oils were used as the flavouring agents. As before, the selected colour should optimally match the chosen flavour.

For example, if gargles. These two subcategories are briefly the drug has a bitter taste, linctuses described below. It should be noted that linctuses Linctuses are now commonly formulated as Linctuses are viscous preparations that sugar-free preparations. The use of elixirs is not common. Linctuses may also be formulated as sugar-free alternatives in which sucrose is replaced by sorbitol and the required concentration of sweetening agent. Formulations designed for this purpose employ water as the vehicle, although a co-solvent, e.

The use of alcohol as a co-solvent may act to enhance the antimicrobial properties of the therapeutic agent. Other formulation components are frequently required to enhance the palatability and acceptability of the preparation.

These include preservatives, colours, flavouring agents and non-cariogenic sweetening agents. Enemas Enemas are pharmaceutical solutions that are administered rectally and are employed to ensure clearance of the bowel, usually by softening the faeces or by increasing the amount of water in the large bowel osmotic laxatives.

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Enemas may be aqueous or oil-based solutions and, in some formulations, the vehicle is the agent that promotes bowel evacuation, e. Aqueous formulations usually contain salts e. Viscosity-enhancing agents, e.

Multiple choice questions 1. Regarding weakly acidic drug molecules, which of the following statements are true? The solubility of weak acids increases as the pH is decreased. The solubility of weak acids increases as the pH is increased. The solubility of weak acids in pharmaceutical formulations may be affected by the presence of counterions. All weakly acidic therapeutic agents exhibit an isoelectric point. Regarding weakly basic drug molecules, which of the following statements are true?

The solubility of weak bases increases as the pH is decreased. The solubility of weak bases increases as the pH is increased. The solubility of weak bases in pharmaceutical formulations may be affected by the presence of counterions. All weakly basic therapeutic agents exhibit an isoelectric point. Regarding the following drug substance, which of the following statements are true? The solubility of the above drug increases as the pH is decreased from pH 9 to pH 4.

The solubility of the above drug increases as the pH is increased from 7 to 9. The above drug may be susceptible to oxidation. The above drug exhibits an isoelectric point. Regarding buffers for pharmaceutical solutions for oral administration, which of the following statements are true?

Citrate buffer is commonly used as a buffer for pharmaceutical solutions. Buffers are required solely to control the stability of therapeutic agents.

Buffer salts may affect the solubility of therapeutic agents. The buffer capacity of a buffer system is increased as the concentration of buffer components is increased.

Regarding the use of antioxidants in pharmaceutical solutions for oral administration, which of the following statements are true? Antioxidants are required in all solution formulations.

Antioxidants reduce the rate of oxidation of the therapeutic agent. The efficacy of antioxidants may be improved in the presence of ethylenediaminetetraacetic acid EDTA. Oral pharmaceutical solutions 23 6. Regarding the use of co-solvents for the formulation of pharmaceutical solutions for oral administration, which of the following statements are true?

Co-solvents are required in all pharmaceutical solution formulations. Alcohols are commonly used as co-solvents in pharmaceutical solutions. Glycerol may directly affect the pH of the formulation.

Co-solvents may affect the viscosity of the solution formulation. Regarding the use of preservatives in pharmaceutical solutions for oral administration, which of the following statements are true? Preservatives are required in all pharmaceutical solution formulations. Preservatives are not required if the solution is manufactured under sterile conditions. Esters of parahydroxybenzoic acid are used as preservatives for pharmaceutical solutions for oral administration.

Preservatives render pharmaceutical solutions for oral administration sterile. Regarding pharmaceutical elixirs, which of the following statements are true? Preservatives are required in all elixir formulations. Elixirs generally require the addition of sweetening agents. Colours are required for all elixir formulations. Regarding pharmaceutical linctuses, which of the following statements are true?

Preservatives are required in all linctus formulations. Linctuses generally require the addition of synthetic sweetening agents.

Linctus formulations may contain high concentrations of sucrose. Colours are required for all linctus formulations. Regarding oral syrups, which of the following statements are true? Preservatives are required in all oral syrups. Sugar-free syrups require the inclusion of a viscosity- modifying agent. Colours are required for all oral syrups. According to this definition may be employed for the administration of drugs by many the solubility of the therapeutic agent potential routes, this class of in the vehicle is low.

The diameter of formulation is predominantly used the disperse phase may range from for the delivery of drugs orally and circa 0. Systems in which parenterally by injection see the particle size diameter falls below Chapter 5. This leads to the main aim of the formulation problems regarding the administration of scientist is to control the process of the correct dosage of the therapeutic separation and, in so doing, optimise agent. The characteristics of an acceptable pharmaceutical suspension include the following: Although low-solubility therapeutic agents may be solubilised and therefore administered as a solution, the volume of the solvent required to perform this may be large.

In addition, formulations in which the drug has been solubilised using a co-solvent may exhibit precipitation issues upon storage. Principles and formulation of suspensions 27 The physical stability of pharmaceutical suspensions As detailed above, pharmaceutical suspensions are fundamentally unstable, leading to sedimentation, particle—particle interactions and, ultimately, caking compaction.

To gain an understanding of the physical stability of suspensions it is necessary to consider briefly two phenomena: It must be stressed that this is only a brief outline and the reader should consult the companion textbook in this series by David Attwood and Alexander T Florence FASTtrack: Physical Pharmacy: Pharmaceutical Press; for a more comprehensive description of this topic.

These are addressed independently below. Ionisation of functional groups Insoluble drug particles may possess groups at the surface that will ionise as a function of pH, e. In this situation the degree of ionisation is dependent on the pKa of the molecule and the pH of the surrounding solution.

Adsorption of ions on to the surface of the particle Following immersion in an aqueous solution containing electrolytes, ions may be adsorbed on to the surface of the particle. Furthermore, in the absence of added electrolytes, preferential adsorption of hydroxyl ions on to the surface of the particle will occur.

Hydronium ions, by contrast, are more hydrated than hydroxyl ions and are therefore more likely to remain within the bulk medium. Following adsorption of ions on to the surface, a phenomenon referred to as the electrical double layer is established Figure 2. This generates a potential on the surface of the particle, termed the Nearnst potential.

The ions responsible for this potential are termed potential-determining ions. Anions are then electrostatically attracted to the positive surface of the particle. The presence of these anions will repel the subsequent approach of further anions. The Stern plane is characterised by: The magnitude of this is generally less than that at the Stern plane. Figure 2. First layer: The Stern Plane Second layer: Stern potential Ws Potential at the Shear Plane: Electrical neutrality may be achieved at the boundary of the second plane of the electrical double layer, i.

In this the counterions are sufficiently present in this layer to neutralise the net positive charge on the surface of the particle. If the number of counterions in the electrical double layer exceeds the adsorbed ions, the zeta potential will exhibit an opposite charge to that of the Nearnst potential. For example, if the Nearnst potential is positive, the zeta potential may be positive.

In certain circumstances molecules may interact with the charged particle surface via non-electrostatic mechanisms. For example, surface-active agents interact with surfaces via hydrophobic interactions. If the surface-active agents are charged, this will alter the Stern and zeta potentials. In this the magnitude of the Stern potential may be increased i.

There is a reduction in this charge at the shear plane i.

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Similarly, non-ionic surfactants may adsorb to the surface of the particle again via hydrophobic interactions , thereby affecting both the Stern and zeta potentials. The presence of electrolytes directly affects the above situations. As the concentration of electrolyte is increased there is a compression of the electrical double layer. The magnitude of the Stern potential is unaltered whereas the zeta potential decreases in magnitude. As the reader will discover, this approach may be used to stabilise pharmaceutical suspensions.

The relationship between distance of separation and the interaction between particles The interaction between suspended particles in a liquid medium is related to the distance of separation between the particles.

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In principle, three states of interaction are possible: No interaction, in which the particles are maintained sufficiently distant from one another. In the absence of sedimentation this is the thermodynamically stable state. Coagulation agglomeration , in which the particles form an intimate contact with each other. This results in the production of a pharmaceutically unacceptable formulation due to the inability to redisperse the particles upon shaking.

Loose aggregation termed floccules , in which there is a loose reversible interaction between the particles, enabling the particles to be redispersed upon shaking. The overall energy of interaction between the particles Vt can therefore be described as an addition of the energies of attraction Va and repulsion Vr , i.

The attractive forces between particles tend to operate at greater distances than the repulsive forces. In this, three main regions may be observed: Energy of interaction Particle Particle Secondary minimum: The primary minimum.

This is a region of high attraction between particles. Particles that interact at distances corresponding to the primary minimum will irreversibly coagulate and the formulation so produced will be physically unstable. The primary maximum. This region prevents the particles from interacting at close distances the primary minimum.

The magnitude of the primary maximum is affected by the presence and concentration of electrolytes. As detailed previously, increasing the concentration of electrolyte decreases the thickness of the double layer, thereby reducing the zeta potential. This leads to a reduction in the magnitude of the primary maximum and increases the magnitude of the secondary maximum. This effect is also observed following the addition of ionic surface-active agents.

The secondary minimum. The secondary minimum is a region where attractive forces predominate; however, the magnitude of the attraction is less than that at the primary minimum. Particles located at the secondary minimum are termed floccules, this process being termed flocculation. This interaction increases the physical stability of the suspension by preventing the close approach to the primary minimum. Furthermore, the interaction between the particles may be temporarily broken by shaking, thereby enabling the removal of an accurate dose.

The process by which particles are engineered to reside in the secondary minimum is referred to as controlled flocculation. Sedimentation, controlled flocculation and the physical stability of suspensions Thermodynamically a disperse system may be considered to be stable whenever there is no interaction between particles. However, in terms of pharmaceutical suspensions, this state is physically unstable. Particles in a suspension will sediment under the influence of gravity and settle at the bottom of the container, the larger particles reaching the bottom initially and the smaller particles occupying the space between the larger particles.

The particles at the bottom of the container are gradually compressed by the weight of those above and, in so doing, sufficient energy is available to overcome the primary maximum repulsive forces and the particles become sufficiently close to form an irreversible interaction at the primary minimum.

This is referred to as caking. In flocculated systems the rate of sedimentation of the flocs is high and the volume of the sediment produced is large due to the large void volume within the floccule structure. Generally the size of the drug particles used in the formulation of suspensions is sufficiently large to exhibit a useful secondary minimum.

In addition the irregular generally non-spherical nature of suspended drug particles will enhance this property. For particles in which the zeta potential and hence the primary maximum is high, manipulation of the magnitude of the secondary minimum is required controlled flocculation.

Generally this is performed by the addition of the required concentration of electrolyte or ionic surface-active agent. In performing controlled flocculation it must be remembered that if the reduction in the zeta potential and hence the primary maximum is too large, the resistance of particle—particle contact in the primary minimum is reduced. Therefore, irreversible coagulation of the particles may occur. As caking in pharmaceutical suspensions is facilitated by sedimentation, it is of no surprise to note that controlling particle sedimentation may enhance the physical stability of pharmaceutical suspensions.

The equation is as follows: Therefore, as may be observed from the above equation, the rate of sedimentation may be practically decreased by reducing the average particle diameter and increasing the viscosity of the vehicle. The former may be readily manipulated by milling the particles to the required size range whereas the latter may be increased by the inclusion of hydrophilic polymers. These points are addressed at a later stage. This is the ratio of the volume of the sediment Vs to the initial volume of the suspension Vi: The sedimentation volume of deflocculated suspensions is usually small, whereas the F value for flocculated systems is high i.

The degree of flocculation is defined as the ratio of the ultimate sedimentation volume of the flocculated suspension to the ultimate sedimentation volume of the deflocculated suspension. This is usually the preferred measurement as it provides a point of reference, i. Formulation considerations for Tips orally administered suspension Pharmaceutical suspensions are formulations unstable systems that require the addition of excipients and knowledge The formulation of suspensions for oral of the particle size of the dispersed administration requires consideration of both phase to ensure that a stable the physical properties of the therapeutic suspension may be formulated.

General formulation considerations are as Therefore, the formulation scientist follows. Therefore, as the average particle size of suspended particles is increased, there is a dramatic effect on the resultant rate of sedimentation, i. Therefore, the average particle diameter of therapeutic agent used in the formulation of suspensions has major implications in the physical stability of the formulation.

To optimise the stability of the formulation, the particle size should be minimised. This may be performed by either chemical controlled precipitation or physical methods e. A phenomenon that may affect pharmaceutical suspensions and which influences the average particle size is crystal growth sometimes referred to as Ostwald ripening. Small particles have a greater solubility dissolution rate than larger particles when dispersed in an aqueous vehicle.

If there is a change slight increase in the storage temperature, this may enable the smaller particles to dissolve in the vehicle. Crystallisation of the dissolved drug may then occur on the surface of the larger particles, thereby increasing the average diameter of the suspended drug particles. This may therefore have implications regarding the physical stability of the suspension. One method that may be employed to reduce crystal growth is the inclusion of hydrophilic polymers within the formulation.

These adsorb on to the suspended drug particles and offer a protective effect. In light of the potential problems associated with crystal growth, it is customary in formulation development to expose the suspension formulation to temperature cycling e. Wetting properties of the therapeutic agent Insoluble drug particles are hydrophobic and therefore may not be easily wetted, i. To wet fully with an aqueous vehicle the contact angle h , i. The contact angle may be defined in terms of the interfacial tensions between the three phases, i.

In practice this is achieved by the incorporation of surface-active agents into the formulation. It is important to ensure insoluble therapeutic agents are sufficiently wetted, as this will ensure that the particles are homogeneously distributed in the formulation and thereby enable the correct dosage of drug to be removed when required by the patient.

Excipients used in the formulation of suspensions for oral administration As the reader will observe, there is a direct similarity between the types of excipients used for the formulation of suspensions and solutions for oral administration. The major difference between these two categories of formulations is the inclusion of excipients to physically stabilise suspensions. Many of the categories and examples of excipients used for suspensions are the same for suspensions as for solutions.

Vehicle As in oral solutions and related formulations , the most commonly used vehicle for the formulation of pharmaceutical suspensions for oral administration is Purified Water USP. The preparation and specifications of this have been previously detailed in Chapter 1.

In addition to purified water, the vehicle may contain buffers to control the pH of the formulation. Further details of these approaches are shown below. Addition of electrolytes Electrolytes may be employed to control flocculation by reducing the zeta potential and hence the electrical repulsion that exists between particles. In so doing the magnitude of the secondary minimum increases, thereby facilitating the interaction of particles at a defined distance. Buffers are electrolytes and may be used for this purpose; however, other salts can also be used.

To ascertain the correct ionic strength l , a series of formulations containing different concentrations of electrolyte are prepared and the sedimentation volume or degree of flocculation determined.

In flocculated systems the sedimentation volume and degree of flocculation are high. The addition of either insufficient or excess electrolyte will produce physically unstable suspensions that exhibit caking.

These are briefly summarised below. Effect on wetting Surface-active agents decrease the contact angle of insoluble particles, enabling greater wetting by the vehicle. This, in turn, assists product homogeneity and decreases aggregation. Effect on flocculation Surface-active agents, both ionic and non-ionic, can interact with the suspended particles and, in so doing, can affect the magnitude of the zeta potential.

This may lead to the lowering of the primary maximum and an increase in the size of the secondary maximum, thereby facilitating flocculation. The correct concentration of surfactant required to stabilise a suspension may be experimentally obtained in a fashion similar to that described above for electrolytes.

For oral suspensions non-ionic surfactants are preferred, e. The greater toxicity of ionic surfactants precludes their use in oral suspension formulations. The concentrations of surfactants required to stabilise pharmaceutical suspensions are dependent on the physical properties of the dispersed particles e.

Hydrophilic polymers Hydrophilic polymers are commonly used to enhance the physical stability and to affect the flow properties of oral suspensions. These two aspects are detailed below. Effects on the physical stability of suspensions Hydrophilic polymers may adsorb on to the surface of suspended drug particles in pharmaceutical suspensions. Due to their large molecular weight, one section of the polymer chain will adsorb on to the particles, leaving the remainder of the chain to extend into the aqueous vehicle.

As the concentration of polymer in the formulation increases, the thickness of the adsorbed layer of polymer increases. As two polymer-coated particles approach each other, there will be stearic repulsion due to an overlap of the adsorbed polymer chains.

This will prevent the particles coming into close contact at the primary minimum. The concentration of polymer The concentration of polymer affects the density of the adsorbed polymer layer on the surface of the particles. The required concentration of polymer should be that which enhances repulsion but does not prevent the interaction of the particles in the secondary minimum flocculation.

Generally flocculation occurs at a distance which is approximately twice the thickness of the adsorbed polymer layer. The type of polymer The type and hence the chemistry of polymer influences the stabilisation properties of hydrophilic polymers in two ways. Firstly, the chemical structure of the polymer will influence the nature of the adsorption on the surface of the drug particles which, in turn, influences the thickness and integrity of the adsorbed layer.

Secondly, as the interaction between specific groups on adjacent polymer chains is responsible for the stearic stabilisation, the nature of the interacting groups on each chain is important. This ability to interact may effectively maintain the polymer-coated particles at a distance, resulting in the production of a structured floccule. Finally if ionic e.

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Secondarily, the addition of hydrophilic polymers to the aqueous vehicle will increase the viscosity of the formulation. Effect on the rheological properties of oral suspension As detailed in the previous paragraph, increasing the concentration of a hydrophilic polymer within an aqueous vehicle will alter the viscosity of the system. However at higher polymer concentrations, typically of those used in oral suspensions, the flow properties are pseudoplastic shear thinning. In addition, pseudoplastic formulations may also exhibit thixotropy, a time-dependent recovery of the flow properties illustrated in Figure 2.

It is important to understand this property in particular, as this should ideally be minimised to enable the rapid recovery of the rheological properties of the formulation. In the pseudoplastic flow curve, the direction of flow is Rate of shear indicated by arrows. Specific examples that are commonly used include: Only low concentrations of these are required to enhance the viscosity of the formulation. These materials swell in water, resulting in a vehicle that exhibits plastic flow with thixotropy.

Caution should be issued when formulated in the presence of cationic compounds as this may induce flocculation of the dispersed, swollen silicates. Due to this susceptibility, hydrated silicates may be formulated along with hydrophilic polymers to produce formulations with the required consistency. Preservatives Oral suspensions are non-sterile; however there are restrictions on the number and type of microorganisms present in this type of dosage form. Whilst the presence of microorganisms within oral suspensions is allowed, it is essential that highly pathogenic microorganisms, e.

Escherichia coli, are absent. Specifications are defined in the various pharmacopoeias regarding the number and type of microorganisms in oral products solutions and suspensions.

For example, the European Pharmacopoeia states that in oral products E. Examples of preservatives that are employed in oral suspensions include: The concentration is usually 0. When selecting the type and concentration of preservative for inclusion in an oral suspension formulation, the following points should be considered: Certain preservatives, e.

As a result the antimicrobial efficacy of the preservative is decreased. To overcome this problem it is customary to increase the initial concentration of preservative to ensure that, after adsorption to the dissolved polymer, the required free concentration of preservative is available. The type particularly in the case of flavours and the concentrations of these are selected, as before, to provide the necessary aesthetic properties. The details of these have been provided in Chapter 1.

Antioxidants Antioxidants are required in certain pharmaceutical suspensions for oral usage to enhance the chemical stability of the therapeutic agent, where this may be compromised by oxidation. As before Chapter 1 , the chosen antioxidants are compounds that are redox systems which exhibit higher oxidative potential than the therapeutic agent or, alternatively, are compounds that inhibit free radical-induced drug decomposition. Commonly used examples for incorporation into oral suspensions usually at concentrations less than 0.

As for solutions, chelating agents, e. All excipients must be physically and chemically compatible with each Manufacture of suspensions for oral other and with the therapeutic agent. If the suspension is flocculated, high-speed mixing may be employed as the flow properties of the system are pseudoplastic shear thinning; Figure 2.

However, if the formulation has been poorly designed and has poor flocculation properties, high-speed mixing will result in an increase in the viscosity of the product termed dilatant flow. Ultimately this leads to issues regarding the quality of mixing as the increased viscosity may render the product difficult to mix homogeneously. Alternatively, the particle size of the active ingredient may be optimised by particle size reduction techniques prior to incorporation into the vehicle.

If the concentration of these is too high, then the precipitated therapeutic agent requires to be washed with an aqueous solvent. Regarding the stability of pharmaceutical suspensions designed for oral administration, which of the following statements are true? Suspensions are inherently pharmaceutically unstable.

The stability of pharmaceutical suspensions is affected by the particle size of the dispersed drug. The stability of pharmaceutical suspensions is affected by the concentration of buffer salts used. The particle size range of dispersed solids affects the stability of pharmaceutical suspensions. Regarding the rate of sedimentation of pharmaceutical suspensions designed for oral administration, which of the following statements are true?

The rate of sedimentation is increased as the diameter of the dispersed drug particles is increased. The rate of sedimentation is increased as the viscosity of the continuous phase is increased. The rate of sedimentation is affected by the concentration of buffer salts.

The rate of sedimentation may be increased by centrifugation. Regarding the electrical double layer, which of the following statements are true? The zeta potential is principally due to ionisation of the drug particle. The zeta potential for insoluble basic drugs is always positive. Manipulation of the zeta potential may be used to enhance the physical stability of suspensions. Increasing the concentration of added electrolyte enhances the thickness of the electrical double layer.

Regarding the DLVO theory, which of the following statements are true? The zeta potential acts as a repulsion barrier. Particles residing within the primary minimum produce pharmaceutically acceptable suspensions. Alteration of the magnitude of the secondary minimum may be performed by increasing the concentration of electrolyte. Increasing the concentration of hydrophilic polymer in a suspension increases the stability of the suspension by increasing the magnitude of the primary maximum.

Principles and formulation of suspensions 43 5. Regarding the role of surfactants in pharmaceutical suspensions for oral administration, which of the following statements are true? Surfactants decrease the water contact angle of dispersed drug particles. Surfactants promote flocculation. Surfactants with low HLB are used to stabilise oral suspensions designed for oral administrations.

Surfactants increase the viscosity of the continuous phase of pharmaceutical suspensions. Regarding the use of hydrophilic polymers for the stabilisation of pharmaceutical suspensions for oral administration, which of the following statements are true? Hydrophilic polymers stabilise pharmaceutical suspensions by increasing the viscosity of the continuous phase and hence promoting the sedimentation of dispersed drug particles.

Hydrophilic polymers may affect the zeta potential of the dispersed drug. Pharmaceutical suspensions may exhibit thixotropy. Flocculated suspensions exhibit the following properties: A low sedimentation volume. A high degree of flocculation. A high rate of sedimentation. Homogeneity of drug concentration per unit dose. Concerning the manufacture of pharmaceutical suspensions designed for oral administration, which of the following statements are true?

Suspensions for oral administration are prepared under aseptic conditions. Suspensions for oral administration are frequently sterilised following manufacture. High-speed mixing of concentrated suspensions may result in dilatant flow. The particle size distribution of the dispersed drug may be reduced postmanufacture using a ball mill. Concerning the use of pharmaceutical suspensions designed for oral administration, which of the following statements are true?

Suspensions for oral administration are primarily used for administration to children or the elderly. Many antacid formulations are suspensions. Drugs with high aqueous solubility are frequently formulated as suspensions designed for oral administration. Pharmaceutical suspensions designed for oral administration must be coloured. Concerning pharmaceutical suspensions for oral administration, which of the following statements are true? Suspensions for oral administration may require the addition of sweetening agents.

Suspensions for oral administration may require the addition of flavours. The pH of the continuous phase may affect the stability of aqueous suspensions designed for oral administration. Creams are emulsions that offer treatment of external disorders. In addition to greater consistency viscosity and this use emulsions are clinically used for are applied topically.

Creams are pseudoplastic intravenously see Chapter 5 , systems with a greater consistency than, for rectally or orally. In the former system properties of the system. In addition to the emulsion types described above there are further more structurally complex types, termed multiple emulsions.

However, the pharmaceutical uses of these are extremely limited due to their possible reversion to the parent primary emulsion. As the reader will observe later in this chapter, the nature of the excipients and the volume ratio of the two phases used in the formulation of these systems determine both the type and consistency of the emulsion.

Emulsions and creams, akin to pharmaceutical suspensions, are fundamentally unstable systems, which, in the absence of emulsifying agents, will separate into the two separate phases. The emulsifying agents used are principally surface-active agents. Furthermore, if the formulation is designed for external Emulsions are physically unstable systems and indeed are more application to, for example, the skin, unstable than suspensions the formulation must be easily spread The type of emulsion dictates the over the affected area.

If the emulsion is water in oil emulsions may be designed for oral application, the flavour administered orally must be suitable whereas if emulsions Both oil in water and water in oil creams are administered topically.

Following oral administration the oil droplets and hence the drug may then be absorbed using the normal absorption mechanism for oils. The external phase may then be formulated to contain the appropriate sweetening and flavouring agents. For example, the cathartic effect of oils, e. The taste of the oil may be masked using sweetening and flavouring agents. This is by no means straightforward.

Emulsion instability and theories of emulsification Emulsion instability and the role of surface-active agents Emulsions are termed thermodynamically unstable systems. Following dispersion of an insoluble liquid, e.

If the droplet contacts a second droplet, coalescence will occur to produce a single droplet of greater diameter and, in so doing, the surface area of the new droplet will be less than the surface areas of the two individual droplets prior to coalescence. This process will continue until there is complete phase separation, i. An interfacial tension exists at the interface between the two phases due to the imbalance of forces at the interface.

The interfacial tension therefore acts both to stabilise the system into two phases and to resist the dispersion of one phase as droplets within the other phase. The system will therefore attempt to correct this instability; the subsequent coalescence of the droplets reduces the surface area of the interface, thereby reducing DG.

In this fashion the spontaneous coalescence of droplets of the internal phase may be explained. Accepting that a fundamental requirement for the formulation of pharmaceutical emulsions is the dispersal of one internal phase within a second external phase, this relationship provides an insight into one of the mechanisms of stabilisation of emulsions by emulsifying agents.

As the reader will be aware, surface-active agents lower the interfacial tension and therefore, when present in emulsion systems, will partially negate the destabilising effects of the increase in surface area of the disperse phase.

It is important to note that this is not the only mode of emulsification of these agents. Classical studies on the stabilisation of emulsions have shown that the stability of the adsorbed layer was of primary importance. In these studies it was shown that whenever sodium cetyl sulphate a hydrophilic surface-active agent and cholesterol a lipophilic surface-active agent were employed as emulsifying agents, the two agents formed a stable film due to their interaction at the interface.

The mechanical properties of this mixed surfactant film were sufficient to prevent disruption even when the shape of the droplets changed. Furthermore, the close- packed nature of the surface-active agents at the interface resulted in a greater lowering of the interfacial tension that could be achieved by either component when employed as a single emulsifying agent. Further studies have shown that interfacial surfactant films form three-dimensional liquid crystalline layers of defined mechanical structure.

In addition to the mechanical properties of the adsorbed interfacial liquid crystal film, the adsorbed layer may carry a charge which, depending on the magnitude, may offer electrical repulsion between adjacent droplets. The toolbar contains form field tools for adding additional fields. Review the form fields Acrobat created. Add fields using the form field tools in the toolbar. Delete, resize, or arrange the fields as needed. You can add any of the following types of form fields: Barcodes Encode the input from selected fields and display it as a visual pattern that can be interpreted by decoding software or hardware available separately.

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