Naila Arsalan

Solutions: Pharmaceutical solutions can be broadly categorized as liquid preparations in which the selected solvent system is used to dissolve the active pharmaceutical ingredient and various excipients. Pharmaceutical solutions are homogeneous in nature and contain both excipients and APIs for the duration of the formulated product's shelf life. Types of administrations: There are numerous ways to administer pharmaceutical solution including orally, recto vaginally, ophthalmoscopically, parenterally, and orally. The oral liquid dosage form for solutions, which includes aqueous solutions, syrups, and elixirs, is the most popular. Whether an oral solution dosage form can be manufactured depends on the active drug's physicochemical properties(such as solubility) and stability. Composition: The dosage form composition is determined by a drug's necessary solubility as well as its solubility in water and biocompatible water-miscible solvents. For instance, a straightforward aqueous solution can be made if the medication is water soluble. However, an elixir is suitable if it is soluble in a water-alcohol-glycerin co - solvent combination. The most bioavailable form of a medicine is typically one that has been dissolved in water. There is no step of dissolving required before systemic absorption because the medication is already in solution. Types of pharmaceutical solutions: Oral pharmaceutical administration solutions The following are the three main types of solution formulations that are administered orally: 1. Oral solutions 2. Oral syrups 3. Oral elixirs For a local effect, additional solution formulations are also used, such as enemas and mouthwashes. 1. Oral solutions:  To provide systemic absorption of the active pharmaceutical agent, oral solutions are administered to the gastrointestinal tract. Because of the gastrointestinal environment's resilience, oral solutions can be formulated over a wide pH range. Unless there are issues with the solubility or stability of the therapeutic agent, the normal pH of oral solutions is around 7.0. 2. Oral syrups: Syrups are highly concentrated aqueous solutions of sugar or a sugar substitute that typically include a flavoring agent, such as cherry syrup, cocoa syrup, orange syrup, or raspberry syrup. There is an unflavored syrup available that is made up of an aqueous solution containing 85% sucrose. Therapeutic agents can be incorporated directly into these systems or added while the syrup is being prepared.  3. Oral elixirs: An elixir is a clear, hydroalcoholic solution designed for intake. The concentration of alcohol required in the elixir is specific to each formulation and is sufficient to keep all of the other components in solution. Other polyol co-solvents may be used in the formulation for this purpose.  Miscellaneous oral solutions: There are other solution-based dosage forms that are delivered orally in addition to traditional solutions, syrups, and elixirs that includes: 1. Linctuses 2. Mouthwashes/gargles.  Details are as follow: 1. Linctuses: Linctuses are viscous solutions that include the active pharmaceutical ingredient dissolved in a large amount of sucrose and, if necessary, additional sweeteners. Due to their calming effects on the inflamed mucous membranes, oral medications are typically used to treat coughs. Linctuses can also be made as sugar-free substitutes in which sorbitol and the appropriate amount of sweetener are used in place of sucrose. 2. Mouthwashes/gargles: Gargles and mouthwashes are used to treat oral cavity inflammation and infection. Water serves as the vehicle in formulations designed for this purpose, while a co-solvent like alcohol may be used to solubilize the active ingredient. Alcohol used as a co-solvent may improve the therapeutic agent's antibacterial effects. Frequently, additional formulation ingredients are needed to improve the preparation's acceptability and palatability. Preservatives, colors, flavorings, and non-cariogenic sweeteners are a few of these. Solutions other than oral administrations: Enemas: Enemas are pharmaceutical solutions that are given rectally to assure bowel clearance. Typically, they do this by softening the faeces or by increasing the amount of water in the large intestine (osmotic laxatives). Enemas can be made of aqueous or oil-based solutions, and in some formulations, as the arachis oil retention enema, the vehicle itself acts as the agent that encourages intestinal evacuation. Salts (such as phosphates) are typically used in aqueous formulations to change the rectum's osmolality and so promote the passage of fluid to the rectal contents.To help the formulation stay in the rectum and lower the probability of seepage, viscosity-enhancing substances, such as glycerol, may be added. Typical formulation of solutions dosage form: The typical manufacturing process/formulation for solution dosage forms entails simply mixing all ingredients together to form a solution. However, several process variables, such as the sequence of ingredient addition, process equipment and parameters to control foaming and mixing dynamics, and temperature control, must be carefully controlled to ensure a reproducible and high-quality manufacturing process. The typical formulation ingredients of dosage formulations for oral solutions include: Active pharmaceutical agent A vehicle, typically watery but sometimes also made of vegetable oil. A buffer to maintain the desired pH of the solution. A sweetener, flavor, and color to enhance the taste. A taste-mask agent, if necessary. Preservative with antimicrobial properties (s). If and when necessary, antioxidants or other stabilizers (such chelating agents). If and when necessary, co-solvent(s) and/or surfactant(s). When choosing a vehicle, it should take into consideration the functionality, compatibility with other ingredients and the API, and solution stability of the flavor(s), sweetener(s), color(s), preservative(s), and viscosity control agents. In oral solutions, the main carriers include water, ethanol, glycerin, syrups, and various combinations of these. Propylene glycol and polyethylene glycol are examples of aqueous-miscible solvents that are employed in lesser amounts. The majority of the delivery systems utilized for oral solutions work well for topical solutions. Topical solutions may additionally contain small amounts of acetone, isopropanol, propylene glycol, polyethylene glycols, many oils, and various polymers. Typical Excipient used in solutions are: Various excipients are frequently used in the production of pharmaceutical solutions. These are consisting of:  (1) buffers (2) sweetening agents (3) viscosity-enhancing agents. (1) Buffers: Pharmaceutical solutions use buffers to regulate the pH of the formed product and, in doing so, improve its physicochemical performance. main purpose of buffers in solution is: To maintain the therapeutic agent's solubility in the designed product, pH regulation is typically done. Because so many currently available medications depend on pH for their solubility, even little pH changes may have an adverse effect on the therapeutic agent's solubility in the formulation. To improve the chemical stability of goods where the active agent's stability is pH-dependent. Examples are including: Acetic acid and sodium acetate: about 1% to 2% Citrates: 1% to 5% (citric acid and sodium citrate). Phosphates buffer (sodium phosphate and disodium phosphates) approximately 0.8-2%. (2) Sweetening agents: In oral formulations, sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium, and aspartame are the principal sweetening ingredients. (3) Viscosity-enhancing agents: Non-ionic (neutral) polymers include derivatives of cellulose, such as: hydroxyethylcellulose and methylcellulose Polyvinylpyrrolidone - hydroxypropylcellulose sodium carboxymethylcellulose (anionic) and sodium alginate, ionic polymers (anionic). Antioxidants Pharmaceutical solutions often contain antioxidants to improve the stability of therapeutic agents that are susceptible to oxidative chemical breakdown. Included in sodium sulphite, sodium metabisulphite, sodium formaldehyde sulphoxylate, and ascorbic acid for aqueous formulations. Antioxidants like butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and propyl gallate are examples that can be employed in oil-based solutions. Antioxidants are typically used in little amounts (0.2% weight/weight). Preservatives: Pharmaceutical solutions contain preservatives to control the microbial contamination of the formulation. Preservatives should ideally have the qualities listed below: exhibit a wide range of antibacterial action against both Gram-positive and Gram-negative bacteria as well as fungi. Low toxicity and chemical and physical stability throughout the product's shelf life. examples include: (0.1-0.3%) benzoic acid and its salts. sorbic acid (0.05-0.2%) and its salts Parahydroxybenzoic acid alkyl esters (0.001-0.2%). Pharmaceutical solutions often combine two members of this class, typically methyl and propyl parahydroxybenzoates (in a ratio of 9:1). These two preservatives work better together to broaden the antibacterial range. Steps involved in solution formation: The process of creating solutions is not complicated. The usual manufacturing procedure for solution dosage forms consists of merely combining all of the components to form a solution. To achieve a repeatable and high-quality manufacturing process, various process variables, including the order of ingredient addition, process equipment and settings to control foaming and mixing dynamics, and temperature management, must be carefully controlled. PROCESS FLOW Controlled variables: Mixing time RPM Temperature Final volume Mesh size Filtration integrity Process flow of solution manufacturing Process Validation of solutions: They are liquid preparations in which the medications have been dissolved, suspended, or dispersed in an appropriate medium. Typically, the container contains many doses. The Main Tests Included in Validation Are: a) Particle size and size distribution b) Particle shape or morphology c) Microbial count d) Rheology of solvent or vehicle e) PH of the solvent or vehicle outputs being observed So here are some outputs that need to be monitored: a) Appearance b) pH c) Viscosity d) Specific gravity e) Microbial count f) Content uniformity g) Dissolution testing a) Appearance: The finished product's appearance reveals evidence of instability and degeneration. For instance, settling of solid particles in an emulsion or turbidity in a suspension. As a result, the final product's appearance will meet specific specifications. b) Mixing time: The period of mixing or agitation time and the process temperature have a significant impact on how something looks. c) pH: To reduce PH drift, aqueous oral preparations should only be consumed at a specific temperature and after equilibrium has been attained. d) viscosity: Because viscosity influences the pace at which suspended particles settle in suspension and the coalescence of internal phase globules in emulsions, as well as the overall appearance of oral solutions, it is important to measure and validate it properly. e) Specific gravity: A decrease in the product's specific gravity, such as that seen in suspensions, shows the presence of air inside the formulation's structure. f) Microbial limits: The finished product's microbiological count is essential to evaluate because it allows us to determine the preservative for the product's storage. Each liquid oral product has guidelines for the bio toxicity content. g). The homogeneity: The homogeneity of the drug within the solvent system and the dose uniformity in the case of multi - dose formulations are both impacted by content uniformity. Brief summary of process validation of liquid dosage form: Process Equipment Process variables Properties affected by variables Monitoring output Mixing of liquid Kettle & Tank fitted with agitator Capacity of unit, Shape & position of agitation system, Order of addition, Rate of addition, fill volume, mixing speed of agitator, Temperature of liquid, Mixing time. Appearance of liquid, Viscosity of liquid. Potency, Appearance, pH, Viscosity, Specific gravity Mixing & blending of solids Blade mixers & tumblers Capacity of unit, Mixing speed of unit, Shape of unit, position of mixing element within unit, Product load. Particle size of solids, Blending uniformity. Potency, Particle size analysis, Content uniformity of active component. Dispersing Homogenizer, Colloid mill, ultrasonic device Bore opening/ clearance of rotor & stator, Pressure, Rotor speed, Power consumption, Feed rate, Temperature, Dispersion time, Order of mixing Particle size of solids, Viscosity of liquid. Potency, Particle size Distribution, Viscosity, Specific gravity Semi solid: Pharmaceutical semisolids are topically applied drugs with localized and occasionally systemic effects that are applied to the skin or other accessible mucous membranes.  They frequently consist of two phases—oil and water—with the external phase being continuous and the interior phase being scattered. A three-phase system is frequently created by dissolving the active ingredient in either one or both phases. Semisolid dosage forms are typically used for localized drug delivery. Semisolids account for a significant portion of pharmaceutical dosage forms. Semisolids have a three-dimensional structure that is strong enough to give an undisturbed system a solid-like quality, but is also easily deformed and realigned in response to an external force. Modes of administration: Topically, they can be used on the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear lining. Types of semi solids: Drugs that are applied topically to the skin can be divided into two categories: suppositories and local action medications such as creams, gels, and ointments. Examples are including: Ointments: Ointments are semisolid medications designed for skin or mucous membrane administration on the outside. Based on the medication carrier or base employed in their manufacture, ointments can be divided into four categories:  1. Oleaginous or hydrocarbon bases. Petrolatum, white petrolatum, yellow or white ointment, or mineral oil are the main ingredients.  2. Anhydrous or absorbent base. This class of bases can be divided into two groups: the first group includes bases that allow the incorporation of aqueous solutions (in small amounts) with the formation of a water-in-oil emulsion (such as petrolatum and lanolin), and the second group includes water-in-oil emulsions that allow the incorporation of active pharmaceutical ingredients that are oil soluble. Additionally important as emollients are absorption bases. 3. Emulsion or a base that is water soluble. Oil/water (O/W) or water/oil (W/O) emulsion bases are both suitable. Emollient, occlusive, possibly oily, and hard to remove, W/O emulsions are also emollient. O/W emulsions clean easily with water, do not feel greasy, and are not occlusive. 4. water soluble base. The majority are based on polyethylene glycol. Non-occlusive, non-greasy, and washable in water. An example of a water-soluble base would be a gel. Creams: creams have an opaque appearance and are a viscous semisolid emulsion system. Whether the cream is water in oil (W/O) or oil in water (O/W), will determine the formulation's consistency and rheological characteristics. O/W creams are rinsible and non-greasy. They are suitable for the majority of topical uses and are thought to be especially well suited for use on open wounds. Pastes: Pastes are essentially ointments with a significant amount of insoluble solids added. Through direct interactions between the distributed particles and by adsorbing the liquid hydrocarbon percentage of the vehicle on the particle surface, the excessive amount of particulate matter stiffens the system. Gels: Gels are hydrated forms of insoluble drugs in aqueous colloidal suspensions. When a coherent matrix contains a lot of liquid, the result is frequently referred to as jelly. Jellies are non-greasy, translucent, clear semisolid gels. Poultices: This pasty, soft preparation is used externally. They are put on the skin while still warm. Since the purpose of a poultice is to provide warmth to irritated body areas, it must hold heat for a long period of time.  Plasters: When applied on muslin or cotton felt as a backing material, plasters, that are solid or semisolid masses, stick to the skin. Rigid Foams: When air or another gas is emulsified in a liquid phase to the point of stiffening, a system is called a foam. For instance, shaving creams, whipped creams, and shaving cream aerosols. Process of semi solid manufacturing/typical formulation of SSD: Typical formulations contain the Ingredients Used in Semisolid Preparation such as API, bases, antimicrobial preservatives, chelating agents, humectants, perfumes, etc. The choice of suitable raw materials for a formulation development is made on the basis of the drug delivery requirements and the particular need to impart sufficient emollience or other quasi-medicinal qualities in the formulation.  They are made up of two phases (oil and water), one of which is continuous (external) and the other is dispersed (internal). The active ingredient is frequently dissolved in a single phase. The size of the dispersed particles, the interfacial tension between the phases, the partition coefficient of the active ingredient between the phases, and the product rheology, or the flow characteristics of these substances, are few examples of the many physical properties of the dosage form that depend on different variables. Typical excipients used in manufacturing of SSD: Bases: Many medications for external application come in semi-solid forms. There are numerous ways to categories ointment bases, but the following classification based The following compositions are typically used:  Bases for absorption. Emulsion bases, in  Bases that are water soluble Water removable bases.  Preservatives: Although some bases are resistant to microbial attack, but still need an antimicrobial preservative because of their high-water content. Methyl hydroxybenzoate, Propyl hydroxybenzoate, Chlorocresol, Benzoic acid, Phenyl mercuric nitrate, Benzalkonium chloride, Chlorhexidine acetate, Benzyl alcohol, and Mercurial are among the preservatives that are frequently employed. Antioxidants: Antioxidants that are frequently used include butylated hydroxy anisole and butylated hydroxy toluene Chelating Agents: Citric acid and maleic acid are two examples of frequently used chelating compounds. Humectants: Examples of frequently employed humectants are polyethylene glycol, glycerol, and sorbitol. Perfumes: Perfumes Lavender oil, rose oil, lemon oil, and almond oil are a few examples of often used fragrances. Emulsifier: Ideal emulsifier characteristics include, For appropriate emulsification, surface tension must be reduced. It should immediately absorb near the dispersed phase to prevent coalescence. Effective at low concentrations; ability to enhance viscosity at low concentrations.  Gelling Agents:  These are either hydrophilic inorganic compounds or organic hydrocolloids. It includes Tragacanth, sodium alginate, pectin, starch, gelatin, derivatives of cellulose, carbomer, and clays made of polyvinyl alcohol. Enhancers for Permeation: The systemic drug delivery via the transdermal route has, however, significantly risen in popularity with the advent of numerous penetration enhancers. Process flow: 1. Transfer the Materials into large tank: Either the oil phase or the aqueous phase could be used to dissolve the API. It is essential to measure its solubility in order to calculate the appropriate amounts of solvent. The homogeneity of the product is improved by dispersing the active component in a portion of the solvent before adding it to the larger formulation tank. 2. Process controls:  Mixing: when manufacturing a semisolid product, it is typical to need to do several steps of mixing. Achieving product homogeneity is the purpose of the last mixing stage. Type of mixer, mixing techniques (low shear or high shear), and mixing times should all be taken into account during the mixing process. It is crucial to establish the ideal mixing strategies and speeds as well as the necessary level of shear. While the mixing of a gel may require moderate shear in order to preserve certain physical qualities, such as viscosity, emulsification often requires high shear or homogenization to produce the ideal droplet size and dispersion. For each step, the required mixing speeds must be attained at each batch's sizing. Homogeneity: By taking samples from different parts of the mixing vessel and submitting them for evaluations such as pH, viscosity, appearance, and assay, homogeneity is confirmed. Multiple mixing parameters that could affect the homogeneity of the final product are typically assessed throughout development. 3. Controlled temperature: Every step of the process requires a set of temperature limitations. These temperature limitations are established using data on the materials and the temperatures necessary for each operation, and they should be evaluated as part of the product's development before it approaches the approval stage. The product may degrade physically or chemically in the presence of high temperatures. One of the phases may not be properly emulsified at low temperatures. The consistency, appearance, and viscosity of the semisolid dosage form can be affected by either temperature extremes. The product's microbiological quality should be taken into account when controlling temperature. 4. Homogenization: This stage intends to make a homogenous mixture both visually and in terms of the active ingredient's distribution (whether it is suspended or dissolved in the internal phase or droplet size for emulsions).   To accomplish this goal, a variety of homogenizer types could be applied.  These include a high shear mixer (colloidal mill), which consists of one fixed disc inside of a rotating disc, and an open disc mixer with very high tip speeds at the blades. As the coarse particles go through the discs, shear causes the particle size of the coarse particles to decrease. Extremely high speeds or long mixing times would subject the product to excessive shear, which would affect its physical and analytical characteristics, while extremely low values would not provide the desired particle size for a uniform product. 5. Degassing or vacuuming: To get rid of any air trapped inside the product, this step might be completed as one of the last ones in the procedure. This trapped air may affect the product's stability, filling weight, specific gravity, and dosage application. During the vacuum phase, the bulk product is typically mixed at low speed. The minimum vacuum level and the precise vacuum application duration are the process parameters that need to be decided upon and managed in this step. 6. Filling and packing: The semisolid bulk product can be pumped or gravity fed into the filler. A careful selection of filling equipment configuration is essential because in the case of a pump, the materials may have a greater chance of some shear effect, which could affect the viscosity and the release of the drug. Any steps taken to prevent the product from absorbing air should be considered during the material transfer. Filling weights, filling speed, and tube closure parameters are typically the process parameters that need to be determined at this stage. Process flow diagram of semi solid manufacturing Process validation of SSD: Process validation controls the production process's flexibility and constraints in order to achieve desirable qualities in the drug product while preventing unwanted attributes. Validation of Critical Parameters Process Temperature: It is critical for successful manufacturing to process at the proper temperature. Excessive heating during processing can cause chemical degradation, while insufficient heat can cause batch failures, and excessive cooling can cause the precipitation of solubilized ingredients. Heating and Cooling Rates: The success of ointment consistency, for example, is dependent on proper heating and cooling rates. a) Slow heating can result in low yields due to evaporative loss. b) Rapid heating may burn areas of the batch in contact with the heating surface, increasing the possibility of burnt material in the batch. c) Sudden cooling can cause precipitation/crystallization or an increase in viscosity. Methods and Speeds of Mixing: It is critical to determine the required amount of shear as well as the best mixing methods and speeds. Emulsification typically necessitates high shear or homogenization to achieve optimal droplet size and dispersion, whereas gel mixing may necessitate low shear to preserve certain physical properties, such as viscosity. At each batch scale, proper mixing speeds must be obtained for each phase. The amount of shear imparted to initially disperse the polymer into the medium determines optimal hydration. If only very low shear mixing is used, a polymer may never be completely dispersed and hydrated, resulting in an out-of-spec viscosity. DURATION OF MIXING: Identifying the minimum time required for ingredients to dissolve and the maximum mixing time before product failure is required for optimization mixing time (e.g., when viscosity begins to drop). Over-mixing, particularly high shear, can destabilize the structure of polymeric gels, particularly those based on acrylic acid. Over-mixing in an emulsion can cause the product to separate prematurely, resulting in a significant decrease in viscosity. Flow rates: Flow rate optimization entails determining the amount of shear or throughput required. A water-in-oil emulsion, for example, may require a slower addition speed than a traditional oil-in-water emulsion, and the flow rate must be adjusted accordingly. Any product that uses a pump must be handled with caution. If the formulation is pumped too quickly, overhearing can occur. If the pumping rate is too slow, the formulation will spend more time in an in-line homogenizer, exposing it to additional shear. Polymers and gums are introduced: If adding directly to batch, polymers (Carbomers) and gums (Xanthan) must be added in a very controlled manner. Similarly, alternative methods of incorporation include Eductors like Tri-Blenders and Quadro Ytron dispersers, as well as the creation of a polymer or gum slurry in a medium with little to no solubility Semisolid System Unit Operation In the production of semisolid dosage forms, there are five-unit operations. I. Liquid mixing II. Solid mixing III. Semisolid mixing IV. Dispersing V. Milling and size reduction of solid and semisolid Process variables, variables' effects on properties, and liquid mixing output monitoring Process variables, variables' effects on properties, and monitoring output of solids mixing and blending Process variables, variable-affected properties, and semisolid output monitoring Process variables, variable-affected properties, and semisolid output monitoring Process variables, variables' effects on properties, and monitoring output of dispersing Conclusion: Validation is a fully developed quality control instrument for the pharmaceutical industries and a validated assurance of the process's robustness and efficacy. As the items are produced in accordance with pre-optimized manufacturing stages, batch defects are completely eliminated. With the introduction of the notion of validation, it has been simple to maintain the batch consistency of the product while also imparting quality in them. The traditional testing technique at the final step produced significant challenges in maintaining uniformity of each batch.