MODULE 1. GENERAL CONCEPTS OF DRUG TECHNOLOGY. POWDERS. LIQUID DOSAGE FORMS.
CONTENT MODULE 2. LIQUID MEDICAL FORMS.
LESSON 8. PREPARATION OF LIQUID MEDICAL FORMS BY MASS–VOLUMETRIC METHOD BY DISSOLVING SOLID SUBSTANCES AND USING CONCENTRATED SOLUTIONS.
All liquid dosage forms are dispersed systems in which medical substance (the internal phase) is dispersed uniformly though-out the external phase. Medical substances in liquid dosage form can be in the different aggregate states: solid, liquid and gas.
Physical and chemical systems:
real solutions
colloid solutions
suspensions
emulsions
infusions, decoctions, extracts and other.
Solution is a homogeneous mixture composed of two or more substances. In mixture, solute is dissolved in another substance, known as a solvent.
Liquid dosage forms can be classified
by medical aplication:
for internal use – ad usum іnternum
for external use – ad usum externum
for injection – pro іnjectіonіbus.
Liquid dosage forms for internal use name usually mixtures (from the Latin word of mіxturae – to mix up), the disperse phase – water (only). They are measured out to the patients independently by spoons (table (soup)-spoon – 15 ml, dessert-spoon – 10 ml, tea-spoon – 5ml.).
By composition
Simple– solutions which include only one substance.
Multiple- solutions which include a few ingredients.
By nature of solvent.
Hydrogen’s
non-aqueous (alcoholic, glycerin, oily).
BASIC TECHNOLOGICAL OPERATIONS FOR PREPARATION LIQUID DOSAGE FORMS
Preparation of liquid dosage forms consists of the followings stages:
1. Selection of bottles and corks.
2. Weighting of medical substances.
3. Measurement of solvent.
4. Dissolution.
5. Percolation or filtration.
6. Packing.
Nomenclature of the concentrated solutions which use for preparation mixtures
5 % solution (1:20) sol. Natrii hydrocarbonatis
10 % solutions (1:10) are sol. Natrii benzoates, sol. Coffeiatrii-benzoatis.
20 % solutions (1:5) are sol. Natrii bromidi, sol. Kalii bromidi, sol. Natrii iodidi, sol. Kalii iodidi, sol. Natrii chloridi, sol. Kalii chloridi, sol. Calcii chloride, sol. Hexamethylentetramini, sol. Cloralii hydrati, sol. Natrii salicylati.
25 % solution (1:4) sol. Magnii sulfati.
For example, it is necessary to prepare 1 L 20% solution of Kalii bromidi.
All calculations can be conducted by two methods:
account the density of this solution
account the coefficient of increase of volume
Account the coefficient of increase of volume :
Quantity of water for preparation of the concentrated solutions, can be expect using the coefficient of increase of volume.
The coefficient of increase of volume (CIV) is coefficient, which shows an increase of the volume of solution at dissolution of a 1,0 gram of solid substance.
For Kalii bromidi CIV is 0,27.
Then 200,0 g of Kalii bromidi at dissolution will occupy a volume 54 ml.
V= 0,27*200,0 = 54
Consequently, for a receipt to a 1 litre of a 20% solution it is necessary to take 946 мл of the cleared water
1000-54=946ml
PREPARATION OF MIXTURES
Rule of preparation mixtures:
At preparation of dosage forms hold to the set procedure of dissolution and mixing of medications taking into account their physical and chemical properties.
Always at first measure a distilled water. In the bottle in distilled water dissolve solid substances in a next sequence – at first narcotic, poisonous, strong affective, then general list. (at first – heavily soluble, and then – easily soluble), If sum of solid substances more than 3 % take into account the coefficient of increase of volume.
Percolation in a small bottle through the double layers of gauze, or tampon
Add the concentrated solutions from the burette system, at first narcotics, after that general list in order according to the prescription
Add not fragrant and non-flying liquids ( syrups, tinctures); then alcoholic liquids, in the order of growth of concentration of alcohol; are fragrant and volatile liquids
Rp: Analgіnі 3,0
Kalіі bromіdі 4,0
Aquae purіfіcatae 200ml
Tіncturae Beladonnae 8ml
Tіncturae Valerіanae 10ml
Mіsсe. Da.
Sіgna. 1 soup-spoon 3 times a day
WCP (reverse side):
Total volume: 200ml+10ml+8ml=218ml.
Concentrated solution Kalіі bromіdі 20% (1:5)
4,0´5=20ml.
Analgіnі 3,0
218 ml – 3,0
100 ml – Х Х = 1,7% (1,7%< 3%)
Aquae purіfіcatae 200-20 = 180 ml
WCP (front side):
Date prescription №
Aquae purіfіcatae 180ml
Analgіnі 3,0
Solutіonіs Kalіі bromіdі (1:5) 20ml
Tіncturae Beladonnae 8ml
Tіncturae Valerіanae 10ml
V total = 218 ml
Has prepared:
Has checked up:
In porcelain cup measure off 180 ml of cleared water and dissolve 3,0 of analgin. Solution percolate through a piece of wool in a small bottle for dispense. There measure off 20 ml of solution potassium bromide (1:5), then tincture of Belladonna, in the last turn measure off the tincture of valerian (prepared on a 70% alcohol). Glue on the number of recipe, label “Mixture”,, “Shake before use “.
Rp: Kalіі іodіdі
Natrіі bromіdі aa 5,0
Glucosі 15,0
Aquae purіfіcatae 180ml
Mіsсe. Da. Sіgna. 1 tablespoon 3 times a day.
At first determine the percentage of the total glucose mixture.
180 ml – 15.0
100 ml – X X = 8,3%, more than 3%.
15.0´0,69=10,35(ml), is much more tolerance than in 3,6 ml.
In this case calculation of amount of water for recipe conduct by such method : the concentrated solution- sodiums bromide 20% (1:5) and potassium bromide 20% (1:5) it is necessary to take for 25ml (5,0 ´ 5=25); water: 180ml-(25ml+25ml+10,35ml)=119,6ml
Technology of preparation following: in porcelain cup measure off 120ml of water (better warm) and dissolve a 15.0 glucose, percolate solution in a small bottle for dispense; there measure off for 25ml 20% solution of potassium iodide and 20% concentrated solution-sodium
bromide. Labels are “Mixture”, to “Keep in a cool place”, number of recipe.
WPC
Date № prescription
Aquae purіfіcatae 120ml
Glucosі 15,0
Solutіonіs Kalіі іodіdі (1:5) 25ml
Solutіonіs Natrіі bromіdі (1:5) 25ml
V total =180ml
Prepared:
Checked:
WPC r.s.
Rp: Kalіі bromіdі
Natrіі bromіdі aa 2,0
Aquae Menthae ad 200ml
Mіsсe. Da. Sіgna. 1 table spoon 3 times a day.
WPC f.s.
Date № prescription
Aquae Menthae 200ml
Kalіі bromіdі 2,0
Natrіі bromіdі 2,0
V tot. = 200ml
Prepared:
Checked:
In the case, when of the recipe as a solvent prescribed flavored water is allowed to use concentrated solutions of powdery substances and Capacity factor of increased do not use.
Technology: measure off 200 ml of water mint and dissolve in it 2.0 sodium bromide and potassium bromide, and then filtered in the bottle for dispensing.
Extemporaneous formulations of Liquids
1. Introduction
Pharmacists and paediatricians are often faced with the problem of modifying an oral dose form intended for adult use into a suitable form for paediatric administration. Texts and research papers freely describe paediatric doses without exploring the logistics of dose administration. Tablets and capsules are generally unsuitable for administration to children aged under four years and a suitable tablet strength might not be available for use in older children. The range of commercially available paediatric oral liquids and tablets is narrow because the relatively specialised use of these products makes industrial product development, manufacture and registration financially unattractive. Availability varies between countries and very few products are available in countries which constitute a small market. There are, however, anomalies to this theory in that some oral liquids (for example, captopril liquid, metronidazole suspension and rifampicin suspension) that are not available in North America are freely available in other countries such as New Zealand.
In the absence of a ready-made product a frequent approach by pharmacists is to prepare an oral liquid from tablets, capsules or powdered drug dispersed or dissolved in a suitable base. These are often referred to as extemporaneously prepared formulations and the practice occurs on an international scale. A survey of 210 pharmacists in the USA identified the eleven most frequently compounded preparations and the authors concluded that efforts by manufacturers and professional associations are required to supply pharmacists with information on the compounding and stability of extemporaneous preparations.1 Stewart and Tucker 2 surveyed Australian hospitals and showed that 116 drugs were extemporaneously compounded into 270 different formulations for paediatric use. Frequent problems identified in this survey included disguising unpleasant taste, achieving dose uniformity and a lack of chemical and physical stability data. This lack of stability information is a common problem and formularies of extemporaneous formulations have been published in an attempt to provide some guidance on the preparation of paediatric oral liquids. The first widely available book was published in the UK in 1978 3 and is mainly a collation of individual
hospitals’ formulas and recommendations made by pharmaceutical companies with little reference to published data. This publication is now considered outdated and obsolete. Over the last 20 years researchers have studied the stability of many extemporaneous formulations and these are summarised in three formularies which have been published in North America.4,5,6 However, the authors of these publications still describe a significant number of formulations which are not based on previously published data which indicates the requirement for further research. Recently more comprehensive books have been published which give much more detail of published stability studies, physicochemical stability data on each drug and some discussion on alternative methods of preparing paediatric doses.7,8
The formulation of an oral liquid for paediatric use requires careful consideration of many factors to ensure that the product is of optimum quality and efficacy. Compounding an oral liquid from crushed tablets should only be considered if there are adequate stability data and it should be recognised that there are often simpler or more reliable methods of preparing the dose. Before discussing the formulation of oral liquids it is important to briefly consider these alternatives some of which are perhaps under utilised.
2. Alternatives to formulation of oral liquids
(i) An alternative drug which is available commercially in liquid form could be selected.
For example, it is usually preferable to use captopril oral solution rather than prepare enalapril solution from tablets.
(ii) Tablet dispersion
The practice of crushing tablets or opening capsules and adding the powder to a palatable drink or sprinkling onto solid food is a time-honoured alternative, but there are few circumstances when this method is appropriate or necessary. It is difficult to ensure that a complete dose has been taken and the practice of nurses or carers handling powdered drug may present health concerns.9 Tablet dispersion is a simpler, more reliable and potentially safer method.9,10
If the tablet disperses in water, it can be dispersed in a small volume and the dose given when a suspension is formed, mixed with a flavoured vehicle if required. Not all tablets disperse readily but some form a suspension in seconds.10
If the tablet disperses readily and the drug is soluble, dispersing the tablet in a known volume of water allows a fractional dose to be accurately measured with a syringe as in the case of captopril.11 As extraction of soluble drug from the tablet excipients may be incomplete12,13 the suspension should be shaken or stirred prior to measuring the dose and not filtered unless it has been established that active drug is not removed. In the case of an insoluble drug, the measurement of a fractional dose by taking an aliquot from a suspension formed in this way cannot be recommended due to probable rapid sedimentation of insoluble drug and resultant dosage inaccuracy. Tablet dispersion may not always be practical for infants when the doses required are the equivalent of small tablet fractions.
(iii) Oral administration of the injection
This is possible for some drugs but there are important factors which must be considered when evaluating whether the injection is suitable for oral use. This can be illustrated with some examples.
(a) If the injectable form of the drug is the same as the oral form (for example labetalol hydrochloride, ondansetron hydrochloride) it can be assumed that the drug will be absorbed from the injectable formulation. However, as the drug is in solution more rapid absorption and higher peak levels may occur compared to slower absorption from a solid dose form.
(b) Some injectable drug forms are produced by reaction of the insoluble oral form with sodium hydroxide to give a soluble salt (for example acetazolamide sodium, sodium folate). In the acidic conditions of the stomach the oral form (acetazolamide, folic acid) will be generated.
(c) The injectable form of drugs which are chemically degraded by gastric acid (for example omeprazole) are unsuitable for oral administration.
(d) The oral use of the injectable form of a drug which is subjected to extensive first-pass metabolism, resulting in poor oral bioavailability, may be impractical due to the large volume required. For example, a volume of 15 mL (15 ampoules) of 1 mg per mL is required if propranolol injection is used to give an oral dose of 15 mg.
(e) Drugs such as cefuroxime and enalaprilat which are administered orally as pro-drugs (cefuroxime axetil and enalapril maleate) have relatively poor bioavailability and are not suitable for oral administration.
(f) Injections may contain excipients and adjuvants that are undesirable in some patients. For example proplylene glycol and ethanol.14
(g) The cost of using the injectable form orally may be prohibitive. For example, the cost of giving dantrolene injection orally is approximately 60 times the cost (per mg of drug) of using the oral form.
(v) Powder Papers or Repacked Capsules
Fractional doses can be prepared by repacking dosage aliquots of powdered tablets or capsule contents, or mixing with a diluent such as starch or lactose prior to repacking into powder papers or empty capsules. This method can be used for drugs which are unstable in aqueous solution and was used to prepare paediatric doses of captopril before a stabilised solution was made commercially available.15 These methods can still significantly compromise drug stability and extreme care must be taken in ensuring uniform drug distribution. Further limitations are the time and cost of the operation and inflexibility of dosage. There are few situations where this option is necessary.
3. Preparation of Oral Liquids; Practices and Problems.
If alternatives are not possible or the convenience and flexibility of a ready prepared product is preferred an extemporaneously compounded oral liquid might be considered.
The most frequently used method is to grind the required number of tablets to a fine powder in a mortar and form a slurry by adding a small volume of water. Excipients such as antimicrobial preservatives, suspending agents and flavouring agents are added to make the final product. A frequently used base is a mixture of glycerol or syrup, a suspending agent
such as methylcellulose, and para-hydroxybenzoates (parabens) as a preservative. Other agents sometimes added include alternative solvents such ethanol, particularly when the drug is poorly soluble in water, and buffer systems to provide the optimum pH for drug stability or activity of the antimicrobial preservative. Whilst ostensibly simple, such formulations can be complex comprising a mixture of the base and a suspension or solution (usually a combination of both) of tablet excipients and active drug. If the drug is water soluble there is a temptation to filter out the insoluble tablet excipients to leave a clear solution but filtration can remove significant amounts of drug if extraction from tablets is incomplete.12,13 Insoluble tablet excipients are in suspension and may compromise product appearance whereas soluble excipients may reduce drug stability, for example, by altering the pH of the preparation.16 Thus there may be several advantages in using pure drug powder instead of tablets but the powder may not be easily obtainable.
The expiry date or “shelf-life” of an extemporaneously prepared oral liquid is assigned empirically or based on published information on a particular formulation. A conservative approach must be adopted when assigning an expiry date because of lack of information on drug stability or limitations in either the design or the conclusions of a published report. Also, it may be impractical to entirely reproduce the conditions of a study which was performed in another institution or country under the controlled conditions of an experiment rather ran clinical use. Most studies base their expiry date recommendation on chemical stability but do not address possible physical or microbiological spoilage which may be significant during actual use of the product. For these reasons it is the author’s opinion that extemporaneously prepared oral liquids should only be used for a maximum of one month from the date of preparation to minimise any unrecognised product deterioration. Longer expiry dates may be applied if more extensive testing is performed.
Finally, when deciding on a formulation it is important to consider any possible adverse effects of the “inactive” components of the preparation. Sucrose (in syrup) can promote the formation of dental caries, ethanol can cause hypoglycaemia and para-hydroxybenzoates can cause hypersensitivity reactions and exacerbate the symptoms of asthma.14 It has also been suggested that benzoates and para-hydroxybenzoates can aggravate neonatal hyperbilirubinaemia by displacing bilirubin which is bound to plasma proteins but this effect has not been demonstrated in vivo14 and the amounts present in oral formulations are
unlikely to pose any risk.17 Limits for the inclusion of ethanol in paediatric formulations have been proposed by the American Academy of Pediatrics.18
Deterioration of an oral liquid may be due to chemical, physical or microbiological instability which can lead to a sub-therapeutic dose of drug, exposure to toxic degradation products or ingestion of unacceptable numbers of micro-organisms. It is important for pharmacists, clinicians and nursing staff to be aware of potential problems caused by instability to ensure that drug therapy is effective and safe.
Chemical instability
Drugs in extemporaneously prepared liquids may be susceptible to chemical reactions leading to degradation. The most common reactions are hydrolysis, oxidation and reduction.19 Usually the reaction rate or type is influenced by pH, for example, azathioprine is rapidly hydrolysed to 6-mercaptopurine at alkaline pH but is relatively stable in acidic or neutral conditions.20 Other factors which may increase the rate of reaction include the presence of trace metals which catalyse the oxidation of captopril.21 methyldopa 22 or exposure to light which catalyses the oxidative degradation of 6-mercaptopurine.23 The rate of chemical degradation usually increases with temperature, a factor which is the basis for accelerated stability trials of pharmaceutical formulations. Preparations made from tablets contain excipents such as binders and disintegrating agents in addition to the active drug. These excipients may reduce chemical stability by changing the pH to a value at which more rapid degradation occurs. This probably explains why amiloride solution prepared from pure drug is more stable than an oral liquid prepared from tablets.16
The drug in the preparation may be totally or partially in solution or predominantly in the solid state as a suspension. Drugs in solution are more susceptible to chemical degradation than drugs in the solid state (ie. suspensions), thus suspensions of acetazolamide and chlorothiazide are more stable than solutions.24,25 However it cannot be assumed in all cases that an extemporaneously prepared suspension is more stable than a solution. In a suspension, an equilibrium exists between drug in the solid state and drug in solution and even though the amount of drug dissolved may be minimal the conditions could be optimal.
for degradation. Frusemide is a notable example which undergoes hydrolysis in acidic conditions where the solid state is predominant, but is much more stable at alkaline pH where it is totally in solution.26
Microbiological Instability
Microbial growth in an oral liquid may cause foul odour and turbidity and adversely effect palatability and appearance. High titres of micro-organisms may be hazardous to health especially in very young or immunocompromised patients. By-products of microbial metabolism may cause a change in the pH of the preparation and reduce the chemical stability or solubility of the drug. Microbial contamination during preparation must be minimised by using clean equipment, sterile water (Water for Irrigation BP) and avoiding contaminated raw materials and containers. If sodium benzoate or benzoic acid are used as antimicrobial preservatives the final pH must be less than 5 so that the active unionised form is predominant.27 Consequently the drug must also be stable at this pH.
Effective preservative systems require rigorous evaluation which is seldom performed on extemporaneous formulations. Many factors can reduce the effectiveness of the preservative including use of contaminated materials, chemical degradation, binding of preservative to suspending agents or tablet excipients, incorrect storage or unhygienic use of the final product..
Physical Instability
Extemporaneously prepared oral suspensions may be susceptible to sedimentation of insoluble drug causing caking. Difficulty in re-suspending the drug or rapid sedimentation following shaking can lead to erratic dosage measurement as demonstrated with chlorothiazide suspension 28 and this inherent problem with extemporaneously prepared formulations is of considerable concern. Some spironolactone suspensions have been reported to be excessively thick and almost un-pourable.29 Refrigeration, whilst usually desirable to maximise chemical stability and reduce microbial growth, can also increase the viscosity of a suspension making re-suspension more difficult 30 or cause the precipitation of active drug or preservatives. It is important to consider the effect on pH of all components of the formulation and the possible impact on stability. Syrup, for example, is relatively acidic
and if used in phenobarbitone sodium oral solution it will cause the precipitation of unionised phenobarbitone.
4. Conclusions
The guide (see below) is an attempt to summarise the many complex issues that have been described and to highlight some of the factors for pharmacists and paediatricians to consider in order to optimise drug therapy. Information sources such as specialised formularies, drug stability texts and the advice of pharmaceutical companies are invaluable. Most pharmaceutical companies will attempt to provide stability information and can sometimes recommend a specific formulation. Practitioners must continue to lobby for the development and availability of more paediatric oral liquids and paediatric strength tablets some of which may be obtainable in other countries. In order to make information more accessible investigators of clinical drug use should describe the formulation details of the preparation used in their research. This information is often omitted from the publication and can be extremely difficult to source especially when required rapidly. Investigators engaged in stability studies should aim to make the results of their research universally acceptable by designing simple formulations and avoiding the use of unnecessary or difficult to use ingredients. Valid protocol design for the stability study is essential 31,32 and ideally the study should be carried out on formulations prepared from pure drug as well as tablets and the pure drug formulation used in practice whenever possible.
Finally, sharing information on paediatric formulations and research collaboration should be further encouraged especially between major paediatric hospitals and research centres to ensure that our patients receive the highest quality drug therapy.
Preparation of a Paediatric Oral Liquid-A Guide
• Consider an alternative drug
• Consider an alternative method, for example, tablet dispersion or oral administration of the injection
• Consult the latest information data-bases and publications. Prepare a formulation according to a published study and follow the conditions of this study as closely as possible. Modifications to published formulations are only appropriate if there are no
detrimental effects on stability. A maximum expiry date of one month from preparation is recommended and liquids without an antimicrobial preservative should be given a shorter expiry date.
• If there are no data from a published study consult pharmaceutical manufacturers, other paediatric hospitals and research centres.
• It may be possible to adapt existing information from drug stability texts (e.g. solubility, pH stability profile) or from the formulation details of the injection or oral liquid available elsewhere.
• Monitor use of the product and observe for any signs of physical instability such as colour change or difficulty in re-suspension.
• Provide information to carers to ensure correct use of the product (e.g. storage conditions, use of an oral syringe, shaking before administration).
• Ensure that formulations details are available to all practitioners involved in the patients care to ensure that the product is consistent in appearance and quality. Prescriptions could contain full details of the formula and hospital pharmacists could provide details to their community colleagues.
Solutions
• Solutions are liquid preparations that contain one or more chemical substances (solute/s) dissolved in a solvent or mixture of solvents.
• The solutes may be active or inactive ingredients
• The solutes may be solids, liquids, or gases in their natural undissolved state.
• The most common solvent used in pharmaceuticals is: water;
• alcohol,
• glycerin, and propylene glycol are used as solvents or co-solvents depending on
the product requirements for ……………………… and ……………………….
• Solutions are formulated for administration by various routes such as :
1. Oral solutions (mouth);
2. Ophthalmic solutions (eye);
3. Otic solutions (ear);
4. Nasal solutions (nose);
5. Rectal solutions;
6. Urethral solutions;
7. Epicutaneous solutions (skin);
8. Injectable solutions;
9. Irrigations solutions (used to bathe or flush open wounds or body cavities are termed).
• Certain solutions have special requirements, such as sterility (e.g., injections, irrigations, and ophthalmic solutions).
• The concentration of active ingredients in solutions varies greatly.
• Some solutions are very diluted, whereas others are highly concentrated.
• The concentration of a given solution may be expressed in molar strength, milliequivalent strength, percentage strength, ratio strength, or other expression (e.g., milligrams per milliliter).
• Knowledge the content or concentration of a solution is critical in calculating the volume required to administer a desired dose of drug.
The British Pharmacopoeia (B.P.) 1998 and the European Pharmacopoeia (Ph. Eur.) 1997 define Oral Liquids:
“Liquids for oral use are usually solutions, emulsions or suspensions containing one or more active ingredients in a suitable vehicle; some liquids for oral administration may consist of liquid active ingredients as such they are intended to be swallowed either undiluted or after dilution. These preparations may also be prepared before use from concentrated liquid preparations, or from powders, granules or tablets for the preparation of oral solutions or suspensions using a suitable vehicle. Liquids for oral use may contain suitable antimicrobial preservatives, antioxidants and other excipients such as dispersing, suspending, thickening, emulsifying, buffering, wetting, solubilising, stabilising, flavouring and sweetening agents and colouring matter authorised by the competent authority ……”
Additional subclasses of Oral Liquid are also defined in the B.P.:
§ Oral Solutions are Oral Liquids containing one or more active ingredients dissolved in a suitable vehicle.
§ Oral Suspensions are Oral Liquids containing one or more active ingredients suspended in a suitable vehicle. Suspended solids may slowly separate on standing but are easily redispersed.
§ Oral Emulsions are Oral Liquids containing one or more active ingredients. They are stabilised oil-in-water dispersions, either or both phases of which may contain dissolved solids. Solids may also be suspended in Oral Emulsions.
§ Mixtures are Oral Liquids containing one or more active ingredients dissolved, suspended or dispersed in a suitable vehicle. Suspended solids may separate slowly on standing but are easily redispersed on shaking.
§ Oral Drops are Oral Liquids that are intended to be administered in small volumes with the aid of a suitable measuring device.
§ Elixirs are clear, flavoured Oral Liquids containing one or more active ingredients dissolved in a vehicle that usually contains a high proportion of sucrose or a suitable polyhydric alcohol or alcohols and may contain Ethanol (96%) or a Dilute Ethanol.
Elixirs tend to be used for potent or nauseous drugs. Although ethanol is a widely used solvent in elixirs, high concentrations may produce a pharmacological effect, hence the inclusion of polyhydric alcohols such as glycerol, propylene or sorbitol as co-solvents.
§ Linctuses are viscous Oral Liquids that may contain one or more active ingredients in solution. The vehicle usually contains a high proportion of sucrose, other sugars or a suitable polyhydric alcohol. Linctuses are intended for use in the treatment or relief of cough, and are sipped and swallowed slowly without the addition of water. Linctuses may possess demulcent, antitussive or expectorant properties. Sorbitol is a useful substitute for sucrose in linctuses for diabetics, but it does cause diarrhoea in large quantities.
DOSE VOLUMES OF ORAL LIQUIDS
A 5mL spoon is used as a standard measure for liquid oral medicines and doses are generally administered in multiples of 5mL. Thus 5mL and 10mL are common dosage volumes. The label should bear the phrase, “One 5mL spoonful to be taken ….” or Two 5mL spoonfuls to be taken…”. When a 20mL dosage is to be administered, patients are often provided with a measuring cup which allows for more accurate dosage.
Phrases such as “teaspoonful”, “tablespoonful”, etc. are not to be used.
Traditionally if a dose was prescribed which was less than 5mL or not a multiple of 5mL, the liquid was suitable diluted to achieve a dose volume which was a multiple of 5mL. For “official preparations”, i.e. those described in the pharmacopoeia, appropriate diluents may be specified in the monograph. Suitable diluents for a proprietary preparation are generally listed by the manufacturer in the product’s data sheet. Dilution may affect the stability of a preparation. Nowadays if a dose, which is less than 5mL, is prescribed (e.g. 2 mL), this will be measured using an oral syringe, which is calibrated from 1mL to 5mL divisions. The oral syringe is used in preference to dilution of oral liquids.
PRESCRIBING OF ORAL LIQUIDS
Oral Liquids may be prescribed in either of two ways:
1. As an official preparation. Reference to the British Pharmaceutical Codex 1973 will reveal the complete formula. Nothing extra should be added; it is completely wrong to add anything, which is not in the formula, unless so directed by the prescriber.
2. As an extemporaneous preparation, in which the prescriber names the drugs required, their dose and the type of dosage forms, but does not specify any formula or excipients. In such cases, the pharmacist must decide what wetting agent, suspending agent, etc., are required, and how much. There is no need to refer back to the prescriber regarding the types and concentrations of the excipients. The pharmacist may also be called upon to prepare a suspension of a drug that is only commercially available in tablet form. The required number of tablets are crushed to a fine powder (or the contents of capsules used) and formulated into a stable suspension for oral administration. These are intended primarily for paediatric patients where fractions of the unit dose have been prescribed. Information relating to the most suitable diluents and shelf-life of the product is frequently available from the relevant pharmaceutical company or from hospital drug information centres.
ORAL SOLUTIONS
The main factor to be considered in the preparation of solutions is the solubility of the solute(s) in the required vehicle. The vehicle is usually aqueous but may be oily or alcoholic. Information on solubility will be found in monographs and reference books, and consideration of this information will usually indicate the most appropriate method of preparation.
Solutes exhibiting adequate solubility usually present few problems.
Insoluble or sparingly soluble materials may be brought into solution by a number of formulation techniques. These are:
§ Adjustment of pH
§ Use of cosolvents such as alcohol or glycerol
§ Solubilisation
§ Formulation of soluble complexes
In general, the easiest way to prepare a solution is to add the solute to some of the vehicle in a beaker or a measure and then stir. A given weight of small particles will usually dissolve more quickly than the same weight of larger particles. Substances such as potassium permanganate are slow to dissolve and they yield an optically dense solution which makes it difficult to determine when solution is complete. The easiest method in this case is to triturate the crystals in a glass mortar with a small amount of the vehicle. After allowing a few moments for undissolved solid to settle, the supernatant solution is carefully decanted from the solid. A further portion of the vehicle is added and the process is repeated until no undissolved solid remains after decantation.
The resulting solution must then be examined for the presence of extraneous material such as fibres, in order to assess if it requires clarification before it can be used. The standard of clarity applied depends on the mode of use of the product, freedom from particles being more important in the case of injections and eye-drops than with gargles. Clarification is usually achieved by filtration.
MIXTURES
Mixtures are defined in the B.P. as oral liquids containing one or more active ingredients dissolved, suspended or dispersed in a suitable vehicle. Suspended solids may separate slowly on standing but are easily redispersed on shaking. Mixtures may contain soluble substances only (i.e. solutions). In mixtures containing diffusible solids the solids are insoluble but on shaking the powder is evenly dispersed for sufficient time for the patient to obtain a uniform dose. A “Shake the bottle” label is essential for these types of mixtures. Examples of some diffusible solids not requiring suspending agents for aqueous vehicles are bismuth carbonate, compound kaolin powder, magnesium trisilicate, magnesium oxide and light kaolin.
1.
Pharmaceutical
Solutions
Solutions are:
Dosage forms prepared by dissolving the active ingredient(s) in an
aqueous or non aqueous solvent.
Solutions can be formulated for different routes of administration
Orally: Syrups, elixirs, drops
In mouth and throat: Mouth washes, gargles,
throat sprays.
In body cavities: Douches, enemas, ear drops,
nasal sprays.
On body Surfaces: Collodions, lotions.
Advantages of SoIutions
(1) Easier to swallow therefore easier for:
children – old age – unconscious people.
(2) More quickly effective than tablets and capsules.
(3) Homogenous therefore give uniform dose than
suspension or emulsion which need shaking.
(4) Dilute irritant action of some drugs (aspirin, Kl, KBr)
minimize adverse effects in the GIT like KCl.
Disadvantages of SoIutions
(1) Bulky therefore difficult to transport and store.
(2) Unpleasant taste or odours are difficult to mask.
(3) Needs an accurate spoon to measure the dose.
(4) Less stable than solid dosage forms.
major signs of instability:
colour change,
precipitation
microbial growth
chemical gas formation
Additives
• Buffers
To resist any change in pH
• Isotonicity modifiers
• Solutions for injection
• Application to mucous membrane
• Large-volume solutions for ophthalmic application
Most widely used isotonicity modifiers are: dextrose and NaCl
• Viscosity enhancement
It is difficult for aqueous-based topical solutions to remain on the skin or in the eye (why?) therefore low concentrations of jelling agents are added to increase the viscosity of the product.
• Preservatives
Solution may become contaminated for a number of reasons:
1. Raw materials used in the manufacture of solutions are excellent growth media for bacterial substances such as gums, dispersing agents, sugars and flavors
2. Equipment, environment and personnel contribute to product contamination.
3. Consumer use may result in the introduction of microorganism.
è a preservative should be added to the product
Preservative used should be:
1. effective against a wide spectrum of microorganisms
2. stable for its shelf life
3. non toxic, non sensitizing
4. compatible with the ingredients in the dosage form
5. free of taste and odour
Preservatives may be used alone or in combination to prevent the growth of microorganisms.
Alcohols
Ethanol is useful as a preservative when it is used as a solvent.
It needs a relatively high concentration (> 10%) to be effective.
Propylene glycol also used as a solvent in oral solutions and
topical preparations. It can function as a preservative in the
range of 15 to 30%. It is not volatile like ethanol.
Acids
Benzoic acid and sorbic acid have low solubility in water.
They are used in a concentration range from 0.1 % to 0.5%.
Only the non-ionized form is effective and therefore its use is
restricted to preparations with a pH below 4.5 (WHY?).
Esters
Parabens are esters (methyl, ethyl, propyl and butyl) of p-hydroxybenzoic acid.
They are used widely in pharmaceutical products and are effective and stable over a pH range of 4 to 8.
They are employed at concentrations up to about 0.2%. Frequently 2 esters are used in combination in the same preparation WHY?
– To achieve a higher total concentration
– To be active against a wider range of microorganisms.
Quaternary Ammonium Compounds
Benzalkonium chloride is used at a relatively low concentration 0.002 to 0.02%.
This class of compounds has an optimal activity over the pH range of 4 to 10 and is quite stable at most temperatures.
Because of the cationic nature of this type of preservative it is incompatible with many anionic compounds.
• Antioxidants
Vitamins, essential oils & almost all fats and oils can be oxidized. Oxidation reaction can be initiated by:
1. heat: maintain oxidizable drugs in a cool place
2. light: use of light- resistant container
3. heavy metals (e.g. Fe, Cu): effect of trace metals can be
minimized by using citric acid or ethylenediamine tetraacetic
acid (EDTA) i.e. sequestering agent .
Antioxidants as propyl & octyl esters of gallic acid, tocopherols or vitamin E, sodium sulfite, ascorbic acid (vit. C) can be used.
• Sweetening agents
Sucrose is the most widely used sweetening agent.
Advantages: Colourless, highly water soluble, stable over a wide pH range (4-8), increase the viscosity, masks both salty and bitter taste, has soothing effect on throat.
Polyhydric alcohols (sorbitol, mannitol and glycerol) possess sweetening power and can be used for diabetic preparations.
• Flavours and perfumes
Mask unpleasant taste or odour
Enable the easy identification of the product.
Natural products: fruit juices, aromatic oil (peppermint, lemon)
Artificial perfumes are cheaper, more readily available and
more stable thaatural products.
Stability of solutions
Both physical and chemical stability of solutions in their containers is very important
A solution must retain its clarity, colour, odour, taste and viscosity over its shelf life.
Classification of Solutions According to Vehicle
(a) Aqueous solutions
(b) Non-aqueous solutions
Aqueous Solutions
Aqueous solutions are homogeneous mixtures that are prepared by dissolving a solid, liquid or gas in an aqueous medium (vehicle).
Vehicle: This may be water, aromatic water or extracts.
WATER
Water is used both as vehicle and as a solvent for the desired flavoring or medicinal ingredients.
Advantages: Tasteless, odourless, lack of pharmacological activity, neutral and very cheap
Tap Water
It is not permitted to use tap water for the dispensing of pharmaceutical dosage forms due to its possible bacterial contamination and the presence of dissolved salts that destroy the active ingredients or enhance their decomposition.
Freshly Boiled and Cooled Water
Boiling is seldom used to destroy vegetative bacteria. But, on storage for long time spores may yield vegetative microorganism.
Purified Water
Must be used for most pharmaceutical operations and in all the tests and assays.
Such water is prepared by distillation, deionization or reverse osmosis.
“Hard” waters are those that contain the Ca and Mg cations.
“Alkaline” waters are those that contain bicarbonates as the major impurity.
Ultraviolet energy, heat or filtration (Millipore filtration) can be used to remove or kill the microorganisms present in the water.
Water for injection
Must be used for the formulation of parental solutions.
It is obtained by sterilizing pyrogen-free distilled water.
Aromatic waters (medicated waters) are clear, saturated aqueous solution of volatile oils or other aromatic or volatile substances.
They are used principally as flavored or perfumed vehicles.
Volatile oils solutions represent an incompatibility problem of
salting out. This occurs after the incorporation of a very soluble
salt in their solution.
Aromatic water will deteriorate with time therefore:
– should be made in small quantities
– protected from intense light and excessive heat by storing
in air tight, light resistant containers.
If they become cloudy or otherwise deteriorate; they should be
discarded. Deterioration may be due to volatilization, decomposition or mould growth.
There are 2 official methods of preparation:
(a) Distillation process (Stronger Rose Water NF)
Adv.: most satisfactory method Dis.: slow and expensive
The drug should be coarsely ground and mixed with sufficient
quantity of purified water in the distillation unit.
After distillation any excess oil in the distillate is removed by
filtration.
Drug should not be exposed to the action of direct heat during
distillation; otherwise, the odour of the carbonized substance
will be noticeable in the distilled aromatic water.
If the volatile principle in the water are present in small
quantities the distillate is returned several times to the still with
fresh portions of drug.
(b) Solution process (Peppermint water)
Aromatic water may be prepared by shaking volatile substance with purified water. The mixture is set aside for 12 hours & filtered. Talc (inert) may be used to increase the surface of the volatile substance, insure more rapid saturation of the water and act as a filter aid.
Methods of Preparation of Solutions
(a) Simple Solution
(b) Solution by Chemical Reaction
(c) Solution by Extraction
(a) Simple Solution
Ø Solutions of this type are prepared by dissolving the solute in a suitable solvent (by stirring or heating).
Ø The solvent may contain other ingredients which stabilize or solubilize the active ingredient e.g. solubility of Iodine is 1: 2950 in water however, it dissolves in presence of KI due the formation of more soluble polyiodides (KI.I2 KI.2I2 KI3.I3 KI.4I4) .[ Strong Iodine Solution USP (Lugol’s SoIution)].
(b) Solution by Chemical Reaction
These solutions are prepared by reacting two or more solutes with each other in a suitable solvent e.g. Calcium carbonate and lactic acid used to prepare Calcium lactate mixture. WHY?
(c) Solution by Extraction
Plant or animal products are prepared by suitable extraction process. Preparations of this type may be classified as solutions but more often, are classified as extractives. Extractives will be discussed separately.
Pharmaceutical Solutions
Aqueous
1. Douches
2. Enemas
3. Gargles
4. Mouthwashes
5. Nasal washes
6. Juices
7. Sprays
8. Otic solutions
9. Inhalations
Sweet &/or Viscid
1. Syrups
2. Honeys
3. Mucilages
4. Jellies
Nonaqueous
1. Elixirs
2. Spirits
3. Collodions
4. Glycerins
5. Liniments
6. Oleo Vitamin
Aqueous Pharmaceutical Solutions
Douches
« Douche is an aqueous solution, which is directed against a part or into a cavity of the body.
« It functions as a cleansing or antiseptic agent.
« Eye douches are used to remove foreign particles and discharges from the eyes. It is directed gently at an oblique angle and is allowed to run from the inner to the outer corner of the eye.
« Pharyngeal douches are used to prepare the interior of the throat for an operation and to cleanse it in supportive conditions.
« Similarly, there are nasal and vaginal douches.
« Douches most frequently dispensed in the form of a powder with directions for dissolving in a specified quantity of water.
Enemas
« These preparations are rectal injections employed to:
§ evacuate the bowel (evacuation enemas),
§ influence the general system by absorption (retention enemas) e.g. nutritive, sedative or stimulating properties
§ affect locally the site of disease (e.g. anthelmintic property)
§ they may contain radiopaque substances for roentgenographic examination of the lower bowel.
« Retention enemas are used in small quantities (about 30ml) and are thus called retention microenema.
« Starch enema may be used either by itself or as a vehicle for other forms of medication
Gargles
« Gargles are aqueous solutions frequently containing antiseptics, antibiotics and/or anesthetics used for treating the pharynx (throat) and nasopharynx by forcing air from the lungs through the gargle, which is held in the throat; subsequently, the gargle is expectorated.
« Many gargles must be diluted with water prior to use. Although mouthwashes are considered as a separate class of pharmaceuticals many are used as gargles, either as is, or diluted with water.
« The product should be labeled so that it cannot be mistaken for preparations intended for internal administration.
Mouthwashes
Mouthwashes can be used for therapeutic & cosmetic purposes
« Therapeutic mouthwashes can be formulated to reduce plaque, gingivitis, dental caries and stomatitis.
« Cosmetic mouthwashes may be formulated to reduce bad breath through the use of antimicrobial and/or flavoring agents.
Mouthwashes are used as a dosage form for a number of specific problems in the oraI cavity; e.g.
mouthwashes containing:
« combination of antihistamines, hydrocortisone, nystatin and tetracycline have been prepared for the treatment of stomatitis,
a painful side effect of cancer therapy.
« Allopurinol used for the treatment of stomatitis,
« pilocarpine for xerostoma (dry mouth)
« tranexamic acid for the prevention of bleeding after oral
surgery.
« carbenoxolone for the treatment of orofacial herpes simplex
infections
Mouthwashes generally contain four groups of excipients
AIcohols: (10-20% in MW) Ÿ may function as a preservative.
aids in masking the unpleasant taste of active ingredients,
functions as a solubilizing agent for some flavoring agents
Humectants: such as glycerin and sorbitol (5-20% in MW)
• increase the viscosity of the preparation
• enhance the sweetness of the product
• improve the preservative qualities of the product.
Surfactants: Non ionic and anionic surfactants aid in the solubilization of flavors and in the removal of debris by providing foaming action. Cationic surfactants such as cetylpyridinium chloride are used for their antimicrobial properties, but these tend to impart a bitter taste.
Flavours: are used in conjunction with alcohol and humectants to overcome disagreeable tastes. The principle flavoring agents are peppermint, cinnamon, menthol or methyl salicylate.
CoIouring agents: also are used in these products.
Nasal Solutions
Nasal solutions are usually aqueous solutions designed to be administered to the nasal passages in drops or sprays.
§ Ephedrine Sulfate or Naphaxoline Hydrochloride Nasal Solution USP are administered for their local effect to reduce
nasal congestion
§ Lypressin Nasal Solution USP for its systemic effect for the
treatment of diabetes insipidus
• The current route of administration of peptides and proteins is limited to parental injection because of inactivation within the GIT. As a result there is considerable research on intranasal delivery of these drugs such as insulin.
• Intranasal drug administration offers rapid absorption to the systemic circulation. This route is safe and acceptable alternative to the parental administration
• There is a direct route of transport from the olfactory region to the central nervous system (CNS) without prior absorption to the circulating blood. The olfactory receptor cells are in contact with the nasal cavity and the CNS and they provide a rout of entry to the brain that circumvents the blood brain barrier
• Commercial nasal preparations include antibiotics, antihistamines and drugs for asthma prophylaxis.
• Current studies indicate that nasal sprays are deposited in the pharynx with the patient in an upright position.
• Drops spread more extensively than the spray and three drops cover most of the walls of the nasal cavity, with the patient in a supine position and head tilted back and turned left and right.
• Nasal decongestant solutions are employed in the treatment of rhinitis of the common cold and for allergic rhinitis (hay fever) and for sinusitis.
• Their frequent use or their use for prolonged periods may lead to chronic edema of the nasal mucosa, i.e. rhinitis medicainentosa, aggravating the symptom that they are intended to relieve. Thus, they are best used for short periods of time used for short periods of time (no longer than 3 to 5 days).
• Nasal solutions are prepared so that they are similar in many respects to nasal secretions, so that normal ciliary action is maintained thus aqueous nasal solutions usually are isotonic and slightly buffered to maintain a pH of 5.5 to 6.5.
Sprays
« Sprays are solutions of drugs in aqueous vehicles and are applied to the mucous membrane of the nose and throat by means of an atomizer nebulizer.
« The spray device should produce relatively coarse droplets if the action of the drug is to be restricted to the upper respiratory tract. Fine droplets tend to penetrate further into the respiratory tract than is desirable.
« Many of the older sprays were prepared by dissolving drug in light liquid petrolatum. This vehicle may retard the normal ciliary action of the nasal mucosa and if drops of oil enter the trachea, can cause lipoid pneumonia. Therefore aqueous sprays, which are isotonic with nasal secretions and of approximately the same pH are to be preferred (WHY?). Such sprays may contain antibiotics, antihistamines, vasoconstrictors, alcohol, and suitable solubilizing and wetting agents.
« They are used for the treatment of allergy and/or vasodilatation (congestion) that occur with common cold.
Otic Solutions
« The main classes of drugs used for topical administration to the ear include local anesthetics, e.g.: benzocaine; antibiotics e.g.; neomycin; and anti-inflammatory agents, e.g.; cortisone.
« These preparations include the main types of solvents used, namely glycerin or water.
« The viscous glycerin vehicle permits the drug to remain in the ear for a long time.
« Anhydrous glycerin, being hygroscopic, tends to remove moisture from surrounding tissues, thus reducing swelling.
« Viscous liquids like glycerin or propylene glycol either are used alone or in combination with a surfactant to aid in the removal of cerumen (ear wax).
« In order to provide sufficient time for aqueous preparations to act, it is necessary for the patient to remain on his side for a few minutes so the drops do not run out of the ear.
« For a Middle Ear Infection:
While the person receiving Otic solution lies on his/her side, the person giving the drops should gently press the (TRAGUS (4 times in a pumping motion. This will allow the drops to pass through the hole or tube in the eardrum and into the middle ear.
« For an Ear Canal Infection
« While the person receiving the medication lies on his/her side, the person giving the drops should gently pull the outer ear upward and backward. This will allow the ear drops to flow down into the ear canal.
Sweet &/or Viscid Pharmaceutical Solutions
These include Syrups, Honeys, Mucilages, and Jellies. All of these preparations are viscous liquids or semisolids. The sweetness and viscid appearance are given by sugars, polyols, or polysaccharides (gums).
SYRUPS
Syrups are concentrated solutions of sugar such as sucrose in water or other aqueous liquid.
simple syrup: when water is used alone for making syrup.
medicated syrup: when the aqueous preparation contains
some added medicinal substance
flavored syrup: which contains aromatic or pleasantly
flavored substances and is intended to be
used as a vehicle or flavor for prescriptions
Polyols (e.g. glycerin or sorbitol) may be added to
– retard crystallization of sucrose or
– increase the solubility of added ingredients.
Alcohol often is included as
– preservative
– solvent for volatile oils.
Syrups possess remarkable masking properties for bitter and saline drugs.
It is important that the concentration of sucrose approaches but not quite reach the saturation point, WHY?
§ In dilute solutions sucrose provides an excellent nutrient for molds, yeasts, and other microorganisms.
§ In concentration of 65 % by weight or more the solution will retard the growth of such microorganisms (WHY?).
§ A saturated solution may lead to crystallization of a part of the sucrose under conditions of changing temperature.
When heat is used in the preparation of syrups, there is almost certain to be an inversion of a slight portion of the sucrose.
C12H22O11 2 C6H12O6
Sucrose heat & acid Invert sugar
(dextrose and levulose)
The speed of inversion is greatly increased by acids (why ?);
the hydrogen ion acts as a catalyst in this hydrolytic reaction.
Invert sugar
D is more readily fermentable than sucrose
D tend to darken in color
C retard the oxidation of other substances.
The levulose formed during inversion is sweeter than sucrose; therefore the resulting syrup is sweeter than the original syrup.
When syrup is overheated it caramelizes.
Invert Syrup:
è It is prepared by hydrolyzing sucrose with hydrochloric acid and neutralizing the solution with Ca or Na carbonate.
è The sucrose in the 66.7% w/w solution must be at least 95% inverted.
è The invert syrup, when mixed in suitable proportions with syrup, prevents the deposition of crystals of sucrose under most conditions of storage.
Preparation of Simple Syrup
(a) Solution with heat
« This is the usual method of making syrups:
in the absence of volatile agents or those injured by heat
when it is desirable to make the syrup rapidly.
« The sucrose is added to the purified water or aqueous solution and heated until dissolved, then strained and sufficient purified water added to make the desired weight or volume.
« Excessive heating in the preparation of syrups must be avoided to prevent inversion of sucrose, with increased tendency to fermentation. Syrups cannot be sterilized by autoclaving without caramelization (yellow color).
« The specific gravity of syrup is an important property to identify its concentration. Syrup has a specific gravity of about 1.313, which means that each 100 ml of syrup weighs 1313 g.
(b) Agitation without Heat
« This process is used in those cases where heat would cause loss of valuable volatile constituents.
« The syrup is prepared by adding sucrose to the aqueous solution in a bottle of about twice the size required for the syrup. This permits active agitation and rapid solution.
« The stoppering of the bottle is important, as it prevents contamination and loss during the process.
(c) Addition of a Medicating Liquid to syrup
« This method is resorted to in those cases in which fluid extracts, tinctures, or other liquids are added to syrup to medicate it.
« Syrups made in this way usually develop precipitates since alcohol is often an ingredient of the liquids thus used and the resinous and oily substances dissolved by the alcohol precipitate when mixed with syrup.
« A modification of this process consists of mixing the fluid extract or tincture with the water, allowing the mixture to stand to permit the separation of insoluble constituents, filtering & and then dissolving the sucrose in the filtrate.
èThis procedure is not permissible when the precipitated
ingredients are the valuable medicinal agents.
(d) Percolation
« In this procedure, purified water or an aqueous solution is permitted to pass slowly through a bed of crystalline sucrose, thus dissolving it and forming a syrup a pledget of cotton is placed in the neck of the percolator
« If necessary, a portion of the liquid is repassed through the percolator to dissolve all of the sucrose.
This method is used for the preparation of Syrup USP.
Preservation of Syrups
£ The USP suggests that syrups be kept at a temperature not above 25°C.
£ Preservatives such as glycerin, methyl paraben, benzoic acid and sodium benzoate may be added to prevent bacterial and mold growth, particularly when the concentration of sucrose in the syrup is low.
£ The concentration of preservative is proportional to the free water.
£ The official syrups should be preserved in well dried bottles and stored in a cool dark place.
Dextrose-Based Syrups
« Dextrose may be used as a substitute for sucrose (WHEN?) in syrups containing strong acids in order to eliminate the discoloration associated with inversion.
« Dextrose forms a saturated solution in water at 70% w/v, which is less viscous than simple syrup.
« It dissolves more slowly than sucrose and is less sweet Preservatives are required to improve the keeping qualities of such syrups. Glycerin is added in 30% to 45% v/v as preservative.
Artificial Syrups (Non-Nutritive Syrups)
§ intended as substitutes for syrups and are to be administered to persons who must regulate their sugar and/or calorie intake accurately. e.g. persons suffering from diabetes mellitus.
§ Some early formulae included glycerin, however, glycerin and propylene glycol are glycogenetic substances, i.e. they are materials which are converted into glucose in the body.
§ An example of non–nutritive syrup is “Diabetic Simple Syrup”. It contains compound sodium cyclamate (6% cyclamate sodium and 0.6% saccharin sodium)
However, the cyclamate studies showed that the sweetener could produce cancer in animals and, as a result, this substance was removed from a wide variety of products. Similar studies have been carried out on saccharin. Much research has been done to find a safe synthetic substitute for sucrose. As a result, aspartame which is about 200 times sweeter than sucrose, is being used now in many commercial preparations as the sweetening agent.
Sorbitol-Based Syrups
« Sorbitol which is hexahydric alcohol made by hydrogenation of glucose has been used in the preparation of syrup.
« It is used mostly in the form of a 70% w/w aqueous solution.
« Sorbitol solution is not irritating to the membrane of the mouth and throat and does not contribute to the formation of dental carries.
« Sorbitol is metabolized and converted to glucose; however, it is not rapidly absorbed from the GlT as sugars. No significant hyperglycemia has been found (WHY?); it may be used as component of non-nutritive vehicles.
« Sorbitol solution does not support mold growth. Preservative should be used in solution containing less than 60% w/w sorbitol.
« It is chemically stable and inert with respect to drugs and other ingredients used in pharmaceutical perpetration.
HONEYS
Are thick liquid preparations. At one time, before sugar was available, honey was used as a base, instead of syrup.
There are few official preparations containing honey. e.g. Oxymel, or” acid honey “‘is a mixture of acetic acid, water and honey
MUCILAGES
§ The official mucilages are thick viscid, adhesive liquids, produced by dispersing gum (acacia or tragacanth) in water.
§ Mucilages are used as suspending agents for insoluble substances in liquids; their colloidal character and viscosity prevent immediate sedimentation.
§ Synthetic agents e.g. carboxymethylcellulose (CMC) or polyvinyl alcohol are nonglycogenetic and may be used for diabetic patients.
Jellys
§ Preparations having a jelly-like consistency. They are prepared also from gums.
§ Are used as lubricants for surgical gloves and catheters
§ Lidocaine HCl Jelly USP is used as a topical anaethetic.
Non-Aqueous Pharmaceutical Solutions
Advantages
§ If the drug is not completely soluble or unstable in aqueous medium it may be necessary to use an alternative non-aqueous solvent.
§ Oily solutions of drugs are often used for depot therapy e.g. in muscles
It is essential to test:
toxicity – irritancy – flammability – cost – stability and compatibility of solvents to avoid problems
§ Solvents such as acetone, benzene and petroleum ether are not used for internal products.
§ Internal products may contain ethanol, glycerol, propylene glycol certain oils.
§ For parental products the choice is very limited
§ This section is devoted to four groups of non-aqueous solutions:
§ 1. alcoholic or hydroalcoholic solutions, e.g. elixirs and spirits,
§ 2. ethereal solutions, e.g. the collodions
§ 3. glycerin solutions, e.g. the glycerites,
§ 4. oleaginous soIutions e.g. the liniments, medicated oils, oleo-
§ vitamins, sprays, and toothache drops.
ELIXIRS
§ Are clear, pleasantly flavored, sweetened hydroalcoholic liquids intended for oral use.
§ They are used as flavors and vehicles e.g. Dexamethasone Elixir USP and Phenobarbital Elixir USP.
§ The main ingredients in elixirs are ethanol and water but glycerin, sorbitol, propylene glycol, flavoring agents, preservatives, and syrups are often used in the preparation of the final product.
§ EIixirs contain ethyl alcohol, however, the alcoholic content will vary greatly, from elixir containing only a small quantity to those that contain a considerable portion as a necessary aid to solubility
§ An elixir may contain water and alcohol soluble ingredients.
Incompatibility of elixir:
♦ Alcohol precipitates water soluble substances e.g. tragacanth, acacia agar and many inorganic salts from aqueous solutions.
♦ If an aqueous solution is added to an elixir, a partial precipitation of ingredients may occur. This is due to the reduced alcoholic content of the final preparation.
SPIRITS
§ Alcoholic or hydroalcoholic solutions of volatile substances. The active ingredient may be gas, liquid or solid.
§ Spirits may be used internally for their medicinal value, by inhalation but is mostly used as flavouring agents.
§ Spirits should be stored in tight, light-resistant containers and in a cool place, WHY?
§ Spirits are preparation of high alcoholic strength and when diluted with aqueous solutions or liquids of low alcoholic content turbidity may occur, WHY?
COLLODIONS
§ Are liquid preparations containing pyroxylin (a nitrocellulose) in a mixture of ethyl ether and ethanol.
§ They are applied to the skin by means of a soft brush or other suitable applicator and, when the ether and ethanol have evaporated, leave a film of pyroxylin on the surface.
§ The official medicated collodion, Salicylic Acid Collodion USP, contains 10 % w/v of Salicylic Acid in Flexible Collodion USP and is used as a keratolytic agent in the treatment of corns and warts.
§ Collodion is made flexible by the addition of castor oil and camphor.
GLYCERINS
§ Glycerins or glycerites are solutions or mixtures of medicinal substances iot less than 50% by weight of glycerin.
§ Most of the glycerins are extremely viscous.
§ Glycerin is a valuable pharmaceutical solvent forming permanent and concentrated solutions not otherwise obtainable.
§ Glycerin is used as the sole solvent for the preparation of Antipyrine and Benzocaine Otic Solution USP. As noted under Otic Solutions, glycerin alone is used to aid in the removal of cerumen.
§ Glycerins are hygroscopic and should be: stored in tightly closed containers.
LINIMENTS
§ Are solutions or mixtures of various substances in oil, alcoholic solutions of soaps, or emulsions.
§ They are intended for external application and should be so labeled.
§ They are applied with rubbing to the affected area, the oil or soap base providing for ease of application and massage.
§ Alcoholic liniments are used generally for their rubefaciant and counterirritant effects. Such liniments penetrate the skin more readily than do those with an oil base.
§ The oily liniments are milder in their action and may function solely as protective coatings.
§ Liniments should not be applied to skin that are bruised or broken.
§ Rubefacient
§ a substance for external application that produces redness of the skin e.g. by causing dilation of the capillaries and an increase in blood circulation.
§ Counterirritant
§ a medicine applied locally to produce superficial inflammation in order to reduce deeper inflammation
OLEO VITAMINS
§ Oleo vitamins are fish liver oils diluted with edible vegetable oil or solutions of the indicated vitamins (usually vitamins A and D).
§ The indicated vitamins are unstable in the presence of rancid oils and, therefore, those preparations, should be stored in small, tight containers, preferably under vacuum or under an atmosphere of an inert gas, protected from light.
