Author(s): Lokesh Sharma, Vishal Vats, Nalin Kaushik, Vaishali Saini, Sakshi Garg, Kaushal Arora* and Prabhakar Kumar Verma
Liquid dosage forms are formulations that are administered through oral, parenteral and topical routes. Liquid dosage forms have better patient compliance as compared to other dosage forms hence, mainly used in paediatric patients. Also, during formulation the drugs are uniformly dispensed in liquid dosage form. It masks the taste of bitter, salty and nauseous drugs. This dosage form enhances the drug absorption and in turn, drug bioavailability. During formulation, some non-therapeutic agents (additives) are added that not have any pharmacological potential but still used to enhance the stability, appearance and efficacy of the dosage form to provide better compliance.
Liquid dosage forms are used since past, for rapid and quick absorption of drugs or medicament [1]. This formulation is beneficial for the patients who feel difficulty during intake of solid dosage form (e.g., paediatrics and geriatrics) [2]. Liquid dosage forms are prepared by dissolution of A.P.I (Active Pharmaceutical Ingredients) into a solvent that may be aqueous or non-aqueous which include solutions, suspensions, emulsions etc. The oral route of administration is widely used because of its convenience of self-administration [3].
API or group of APIs can be blended with many excipients such as preservatives, antioxidant, sweeteners, coloring agents, flavoring agents etc. In case of suspensions and emulsions, suspending agents and emulsifying agents respectively, are added for its long- term stability during storage and use [4]. In contrast, liquid dosage forms have an advantage over solid dosage forms as it has no dissolution time and rapidly and efficiently absorbed by GIT [5].
Monophasic liquid dosage forms has only one phase.
Syrups are defined as the concentrated solution in which sucrose is dissolved in purified water. They are sweet in taste and highly viscous. In simple syrups, the sucrose concentration is 66.7% (w/w) [8]. They are classified as
Syrups that contain medicament.
Syrups that are made only for flavoring purpose.
Elixirs are colored, aromatic and hydroalcoholic formulations that are sweet in taste but less viscous. These solutions are formulated by adding ethyl alcohol, water, flavoring agents, syrups and preservatives [9]. Variety of medicated formulations are present in market which contains very potent therapeutic agents like antibiotic elixirs, antihistaminic elixirs, sedative elixirs. Sometime flavoring elixirs are used for flavors as well as vehicles for further formulations [10].
Linctus is concentrated oral preparations used for the treatment of cough. The API used to prepare linctus are demulcents, sedatives and expectorants [11]. Linctus is consumed in their concentrated form but not in dilute, so that maximum and prolonged effect can be obtained. For the preparation of linctus, mostly, simple syrups are used as a vehicle and tolu syrup is used for aromatic odor and as a flavor [12].
Drops are liquid preparation used for the oral administration. Some vitamins such as vitamin A and vitamin D that are water insoluble but are oil soluble are dispensed in the form of drops for better administration. During administration, the dose can be accurately measured, hence, commonly used in pediatric formulation [13].
Lotions are those liquid preparations that are used for topical purposes, applied on the skin without any friction. They can be applied with the help of material such as cotton, gauze etc [14]. They are applied for the treatment of skin related diseases. The medicament used in lotions can be anti-fungal agents like clotrimazole, Eberconazole, etc. It provides cooling, soothing and protective effect, etc [15].
Liniments are topical liquid or semiliquid preparations. These are non-aqueous alcoholic or oily solutions that are applied topically with friction. Alcohols increase the counter-irritant action and drug penetration into the skin [16]. For the preparation of some liniments, Arachis oil is used as it easily spreads on the skin, comparatively [17]. Drugs that are added in liniments have analgesic, rubefacient, soothing, and counter irritant or stimulation properties. They should not be used on the breached or wounded skin as it may cause severe irritation [18].
Gargles are aqueous solutions which are used externally for the prevention and treatment of throat infections. They are prepared in the concentrated form and a direction is mentioned for its use that it should be diluted with warm water prior administration [19]. The mechanism of gargle is that when it comes in contact with the mucous membrane of the throat and remains in contact for some time, it produces its effect within seconds [20].
Throat paints are viscous and liquid formulations used for the treatment of infections of mouth and throat. In this preparation glycerin is taken as a base. They are sweet in taste [21].
Nasal drops are sterile liquid preparations containing solutions or suspensions that are administered in nasal cavity with the help of a dropper [22]. Aqueous drops are preferred instead of oily drops. Ideally it should have neutral pH and its viscosity must be similar to the nasal secretions and should be isotonic [23].
Eye lotions are monophasic aqueous preparations intended for eye washing. They are formulated in concentrated form and directed for its use by dilution with warm water prior use [24]. It should be free from foreign matter and should be isotonic to avoid unwanted irritation in eyes [25].
Eye drops are sterile preparations containing solutions or suspension of API that is administered in the eye with help of a dropper [26]. It is prepared with aqueous vehicle and be isotonic with secretions of lachrymal gland and free from any foreign matter to prevent unwanted irritation [27].
It consists of two phases:
For example: Suspension and Emulsions
Suspensions are biphasic liquid dosage form in which medicament is finely divided into small solid particles that easily gets dispersed in a liquid vehicle. It contains two phases; one of which is dispersed phase and the other is continuous phase [28]. Solid particles behave as dispersed phase while vehicle as continuous phase. Suspensions can be administered through oral or parenteral route as well as used for external purposes [29]. Example: Amoxicillin oral suspension, Insulin Zinc suspension.
Emulsions are biphasic liquid dosage form consisting of two non-miscible liquids i.e., oil and water. Emulsion contains two phases; one of which is dispersed phase and the other is continuous phase [30]. The liquid is converted into globules minutes which is taken as dispersed phase and the liquid into which the globule is dispersed is known as continuous phase [30]. In normal conditions, the immiscible liquids can’t be dispersed for a long time so for the purpose of stability, emulsifying agents are added into the emulsion system. Emulsifying agent forms a film around the globules so that both the phases can be mixed for a long period of time [31].
Emulsions are Classified as Oil in Water type (O/W) Water in Oil type (W/O). Multiple emulsions (O/W/O or W/O/W).
Excipients are the compounds other than active ingredient that are used in the formulation of any dosage form. Excipients are commonly inactive and don’t have any therapeutic value but still needed for the preparation of dosage form [32]. They are inert in nature and not have any therapeutic or pharmacological effect. They can be derived from natural or synthetic source that are included into a formulation for following prospects as:
Liquid dosage form includes solution, suspension and emulsion that are formulated depending upon the nature of active ingredient as well as its solubility and stability [33]. They are also designed as ready to use liquids, as after reconstitution into to liquid and such as syrup, solution, suspension and emulsions. In the liquid formulation many types of excipients are added such as stabilizer, sweeteners and flavoring agents etc [34]. Its selection also plays an important role for the designing of flavoring and effective dosage forms [35].
Selection of excipients are totally dependent on physical and chemical properties, characteristics of drug constituents, dosage forms and on the route of administration [36]. The major concern in development of oral liquid dosage form is active pharmaceutical ingredients. Following are some major challenges occur during development of liquid dosage forms:
The compatibility of excipients in solution account for the same as the compatibility of recipients with a solid-state drug [37]. If the mechanism of degradation is known then the process of selecting a suitable excipient will be easier. To choose a proper excipient, drugs physicochemical properties like pH stability and Pka value should be known [38].
Excipients Used in Formulation of Liquid Dosage Forms Oral liquid dosage form needs a combination of ingredients of different concentrations that perform various functions like solubilization, provides suitable colors, sense of taste and viscosity [41]. Excipients must be compatible and inert and should be stable for a desired period. There are some common excipients that are generally used in preparations like base (vehicle) that may be aqueous or non-aqueous, viscosity builders that enhances viscosity, preservatives that prevent microbial growth, coloring agents that provide elegant appearance to the formulation, flavoring agent that provide flavor like orange tincture, suspending agents used in the formation of suspensions, emulsifying agents used in case of emulsions [42].
Vehicles are also known as base pharmaceutical formulations in which the active pharmaceutical ingredient and other excipients are dissolved. Vehicle are of two types:
Distilled water and purified water obtained by distillation process or any other suitable process are used in the formulation. The water that obtained from nature have so much dissolved impurities [43- 44]. Some inorganic impurities that are dissolved in natural water are potassium, calcium, magnesium, sulphates and bicarbonates but some organic components are barely soluble or maybe present in insoluble state. Microorganisms are also present in natural water and the microbial load in natural water is known as bio-burden [45]. Generally, water for drinking contains less than 0.1% solids. However, drinking water is not preferable for pharmaceutical formulation. United States pharmacopoeia (USP) permits the use of purified water as a vehicle or an element of aqueous formulations instead of parenteral preparations (injections). To obtain purified water suitable processes like distillation, ionexchanger’s (Reverse Osmosis) are used [46].
It is well known solvent for the preparation of pharmaceutical products or dosage forms. In pharmaceutical field, alcohol is the second most useful solvent after water [47].
It is also known as glycerin. It is a clear, colorless and viscous liquid that provides oily sensation during touch. It is sweet in taste, when exposed to air it absorbs the moisture i.e, hygroscopic in nature [48]. It is prepared by the decomposition of animal fats and vegetables and contains approx. 95% of absolute glycerin. It is soluble in all proportions of alcohol as well as in water but not soluble in ether, chloroform, benzene. It is used to prepare various pharmaceutical products such as elixir of phosphoric acid, syrups and tinctures [49].
Propylene glycol play a variety of roles as an extractant, solvent and preservatives in parenteral and non-parenteral pharmaceutical preparations [50].
Contamination of pharmaceutical products by microorganisms is a major problem in aqueous based liquid dosage forms. Preservatives inhibit the growth of microorganisms. Ideally, preservatives must be compatible, effective at lower concentration against possible microorganisms, should be non-toxic and non-reactive with various components of the formulation. They should be stable during the shelf life of the preparations [51].
Most of the preservatives are bacteriostatic in action and can be acidic and non-acidic. Acidic type of preservatives include phenol, benzoic acid, boric acid, and their related salts [52]. Some other neutral preservatives include benzyl alcohol and β-phenyl ethyl alcohol. Preservatives consist of reactive functional groups that has antimicrobial potential but these functional groups led to some unwanted reactions [53].
Antioxidants are efficient excipients that prevent the oxidation of compounds. The impurities that are present in active pharmaceutical ingredients or in excipients act as catalyst for oxidation reactions. Most of the drugs exist in reduced form that’s why they are highly unstable [54]. Drugs that contain phenolic and sulfhydryl group are affected by oxidation because the drug in the ionized form participates in oxidation [55]. E.g., Adrenaline, the only compound that slowly oxidized at pH less than 4 but quickly destroys under alkaline pH conditions. They inhibit the chain reaction with free radicals in the formulation and inhibit free radical propagation cycle. Antioxidants are mixed with chelating agents and the combination produce synergistic effect because these agents act at different steps in oxidative process [56]. Examples: acetone, sodium bisulfite, acetyl cysteine, ascorbic acid, thiourea.
Flavors are mixture of sensations of taste and flavors and involves the blend of physicochemical and physiological actions of substance. Ideally the flavors that are used in the formulation must be nontoxic in nature, properly soluble in the preparation and should be compatible with the liquid formulation [57]. Some flavors that are sweet in nature increases the blood sugar level that may cause harmful effects in the diabetic patients so in those cases, artificial flavors are used. In the aqueous liquid preparation water soluble flavors are added on the other hand, poorly water-soluble flavors are added into non aqueous preparations [58].
Sucrose is an example of sweetening agent. It enhances the thickness of the liquid and also provides a pleasant texture in the mouth [59]. Sucrose causes harmful effect in diabetic patients so, alternate of sucrose, artificial sweetening agents such as sorbitol, saccharine etc. are used in food and pharmaceutical products. These artificial sweeteners faced some challenges over the safety by FDA and instructions in their uses and sales effect in 1969. Sucralose is one of the most popular compounds used as sweeteners due to its excellent sweetness and also a low-calorie compound but it is expensive [60].
Coloring agents are those compounds which provide a color to the formulation. Colors that are used in the liquid dosage form should be certified by FDA as per D&C Act 1940. Some colorants like Sulphur (yellow), riboflavin (yellow), cyanocobalamin (red), ferrous sulphate (bluish green) is of natural origin but not used in pharmaceutical formulations [61]. Now a days, most of the synthetic colors are used in the formulation but some natural minerals and plant source such as red ferric oxide when compounded with zinc oxide powder gives calamine color i.e., characteristic of the skin tone. During selection of the colorant, age of the patient plays an important role because it seems that certain age group prefer certain colors as children prefer a sweet and fruity flavor [62].
Wetting agents are used in pharmaceutical formulation for the routine purposes, and especially used in liquid dosage form to create a homogeneous mixture of solid into liquid vehicle. Wetting process are challenging process due to absorption of air particles on the solid particles surface. Until the air not completely displaced, the solute particles float on the surface of the solvent and at that time the wetting agent remove the air and easily penetrates the liquid into the surface [63]. Aqueous vehicles such as alcohol and glycerol commonly used for the removal of absorbed air from the surface of solid particles but for non-aqueous vehicles mineral oil is frequently used as wetting agents. Surface active agents are those compounds which reduce the non-aqueous interfacial tension. Most commonly used examples of surfactant are “sodium lauryl sulphate”. The (HLB) Hydrophilic-Lipophilic Balance value of wetting agents exists between 7 and 9 [64].
Buffering agents are also known as pH modifier. The pH plays a key role in liquid formulations. These are used to prevent the variation of pH in the formulation that also prevents a large number of changes during storage. The concentration of the buffering agent is sufficient between 0.05M and 0.5M. The suitable buffer can be selected on the basis of the drug stability and excipients in the buffer, compatibility of container and buffers [65].
In most of the cases combination of buffers as compared to individual buffer are used to gain wider ranges of pH. Not all types of buffers are suitable for every preparation, for example boric acid buffer can be used in the preparation of optical and parenteral fluids but not used for oral liquids because of its toxic effect. Solubility of excipients are influenced by the buffers. Some commonly used buffers are carbonates, citrates and tartrates [66].
The selection of an ideal suspending agent for the formulation of suspension is also a critical factor which is based on viscosity and the settling time of particles. Other factors that are considered during selection of an ideal suspending agents are its rheological properties, suspending capacity in the formulation, compatibility with other excipients and economically effective. Examples of suspending agents are natural gums, synthetic gums etc [67].
Flocculating agent prevents the caking of suspension. The solid particles that are dispersed in formulation causes setting down and form a solid cake of substance in the bottom of the container, so to prevent this condition, the flocculating agents are used [68]. Some examples of flocculating agents are starch, sodium alginate etc.
Chelating agents are those that form chelates with metal ions causes activation of their catalyst property in oxidation. These agents have a property of formation of complex with the drugs that are involved in complex compound containing two or more bond and rings in its structure. It protects the API from catalysts that plays a role acceleration in oxidation reactions [69].
Emulsifiers are the compounds that reduce the interfacial tension between the two immiscible liquids, usually water and oil and form a barrier around both the droplets of the immiscible liquids. Emulsifiers contain hydrophilic and lipophilic portions [70].
The ideal properties of emulsifying agents are as follows: they should be nontoxic, economically effective, should not have any harmful effect on body, should not have any therapeutic effects, must be stable to chemical degradation. Some of the examples of emulsifiers are: acacia, stearic acid, lecithin, lanolin alcohols etc [71].
Liquid dosage forms are widely accepted by patients due to better compliance. There are numerous additives are discovered and developed to conquer the limitations of existing marketed liquid dosage forms. But still there are more need to develop more effective and efficient liquid dosage forms for more patient compliance and increased bioavailability.
LS and KA researched and wrote this review. NK, VS, SG and VV design it. PKV provided guidance, critical review and revision of the manuscript. All authors read and approved the final manuscript.
