Theme of lecture: Manufacturing of semisolid dosage forms. Ointments. Gels. Liniments.

Pharmaceutical preparations for treatment of conditions such as rashes, skin irritation, stings, fungal infections etc. are normally supplied in the form of a cream or ointment as this provides an effective means of delivering the active ingredient directly to the required area. Introduction

Semisolid dosage forms are designed for topic application, for treatment wounds and certain mucous membranes. They have the local therapeutic emollient or protective action, or for the drugs penetration through the skin or mucous membranes. They are characterized by: specific rheological properties at certain temperature of storage non-Newtonian type flow certain structural viscosity pseudoplastic or plastic and thixotropic properties.

Positive aspects of semisolid dosage forms: 1. they have a local effect, resorptive activity and provide of a high concentration of medicines in the skin, tissues, in biological fluids and organs of the body; 2. they are the best dosage form for treatment of infected wounds, burns, dermatitis of various etiologies, frostbite, diaper rash, bed sores; 3. ointments may contain substances which are different to the mechanism and direction of medical action;

Positive aspects of semisolid dosage forms: 4. ointments can be used for general effect on the body or selective for certain organs or body systems, such as an ointment "Nitrong", which is used to prevent strokes; 5. the possibility of achieving a high therapeutic effect of ointments due to the concentration of drug substances and due to optimum selection and combination of drugs and excipients; 6. relative ease and safety application of the ointments.

Negative aspects of soft dosage forms: 1. several ointments have limited therapeutic efficacy becouse their inherent unidirectional effect on symptoms; 2. some ointments contain in their composition unstable, ineffective substance or substances which are difficult to standardize; 3. separate formulations of ointments, produced on a hydrophobic basis, cause a pronounced "greenhouse" effect.

Classification of the semisolid drugs and bases: 1. for its affinity to water: - hydrophilic - hydrophobic (lipophilic); 2. for its ability to absorb water and the mechanism of absorption; 3. for the type of disperse systems: - single-phase (solutions, alloys), - two-phase (emulsion, suspensions) - multiphase systems; 4. for its rheological properties at fixed temperature and storage conditions; 5. for the concentration and dispersion of the excipients and /or drugs.

Classification semisolid drug depend on the aggregate state: Ointment (Ointments) Creams (Creams) Gels (Gels) Paste (Pastes) Liniments (Liniments)

Creams - semisolid dosage forms for local use, representing two-or multi-phase dispersions, a dispersion medium which usually has a non- Newtonian type flow and low values of rheological parameters in the set temperature of storage. Ointments are semisolid dosage forms for local use, a dispersion medium which has a non-Newtonian type of flow and high values of rheological parameters in the set temperature of storage.

Gels are semisolid dosage forms for local use, representing one-, two-or multiphase disperse systems with a liquid dispersion medium, the rheological properties of which are caused by the presence of gelling agent in relatively low concentrations. Paste - semisolid dosage forms for local use, which is a suspension containing a significant amount (typically more than 20 % wt.) uniformly distributed at the base solid dispersed phase.

Liniments are semisolid dosage forms for local use, melting at body temperature. Ointments, creams, gels and pastes, which are characterized by this sign, can be attributed to liniment.

Excipients form a simple or complex base: 1. soft-media bases (petrolatum, lanolin etc.); 2. substances which increase the melting point and viscosity of the base (paraffin, spermaceti, hydrogenated vegetable oils); 3. hydrophobic solvents, water and hydrophilic solvents; 4. emulsifiers (sodium laurel sulphate, twins, cholesterol); 5. gelling agents (carbomer, alginic acid and its salts etc.);

Excipients form a simple or complex base: 6. antimicrobial preservatives (benzalkonium chloride, miramistin, cetrimide etc.); 7. antioxidants (α-tocopherol, ascorbic acid); 8. solubilizers (β-cyclodextrin); 9. perfume and deodorant agents (menthol, essential oils); 10. pH regulators (citric acid, sodium phosphate etc.).

Technological stages ointments production 1. Sanitary preparing of facilities; 2. Preparing of the raw material: a) melting of the base b) filtering of the base c) grinding and sieving of medicines, 3. The drugs introduction in the base 4. Ointments mass homogenization 5. Filtering ointments mass 6. Packaging, labelling.

Typical manufacturing process breaks down into four individual operations: Preparation of the oil phase. Flake/powder ingredients, sometimes dry blended in advance, are dispersed into mineral oil or silicone oil. Heating may be required to melt some ingredients. Hydration of aqueous phase ingredients. Emulsifiers, thickeners and stabilizers are dispersed into water in a separate vessel. Heating may be required to accelerate hydration. Forming the Emulsion. The two phases are blended under vigorous agitation to form the emulsion. Dispersion of the Active Ingredient. The active ingredient often makes up only a small proportion of the formulation; this must be efficiently dispersed to maximize yield and product effectiveness.

The Ointment Manufacturing Plants are ideal tools for the production of Ointment, Cream, Lotions, Tooth Paste & other emulsions & homogenizations.

Equipment for the ointments base melting: 1. Tank with ointments base 2. Funnel with filter and heating elements 3. Heating elements 4. Pipeline for the ointment unloading from tank and transfer it in the reactor

Equipment for obtaining ointments mass: Reactor-mixer 1. Body (corps) 2. Cover with hopper, viewing window, valves, nozzles for the various ointments components introduction. 3. Anchor stirrer 4. Stirrer with blades 5. Turbine mixer 6. Shaft

Reactors of the Promvit

Universal Mixer "Yunitron“ 1. Fixed tank 2. Removable mixing nozzle 3. A bottom outlet 4. Shaft 5. Rotating scraper 6. Hole for connecting of the homogenizer or other equipment 7. Cover with hydraulically management

CREAM VACUUM EMULSIFICATION MIXER (Sainty Co) TFZRJ vacuum emulsification blender is specially designed adopting advanced technology of Oversea according to the cosmetic and ointment production technology. The machine is made up of pretreatment boiler, vacuum emulsification blending boiler, vacuum pump, hydraulic system, pouring-out system, electrocontrol system and worktable.

Stage homogenization is necessary to obtain homogeneous mass of ointment. Equipment for homogenization: 1. Roller rubber of the ointment 2. Discs rubber of the ointment 3. Rotary-pulsation apparatus

Roller rubber the ointment 1. Parallel and horizontal rotary shaft-rollers with a smooth surface 2. Hopper 3. Scraper to remove the ointment Rollers rotate at different speed - 38 rpm, 16 rpm 6.5 rpm

Discs rubber of the ointment Consist from two disks. One is fixed with a hopper for loading ointment mass. Another disk rotates. Ointment is rubbed between the discs. The degree of homogenization depends on the distance between the discs.

The diagram of the closed cycle with rotary-pulsation apparatus 1. Tank for obtaining ointment 2. Steam-jacket 3. Motor engine 4. Rotary-pulsation apparatus

Problem at ointment production When added to water, thickening, stabilizing and emulsifying ingredients can form agglomerates which agitators cannot break down. Similarly oil phase ingredients can form lumps which require shear to disperse. Ingredients must be fully hydrated to obtain the required viscosity and develop yield. Partially hydrated materials can build up on the vessel wall, in- tank baffles and parts of the agitator. Agitators cannot sufficiently reduce droplet size to form a stable emulsion. Active ingredients can be temperature sensitive. Cooling of the product before adding the active ingredient further increases processing time. Poor dispersion of the active impairs product effectiveness. Long mixing times and additional equipment may be required to obtain a homogeneous and stable finished product.

Silverson mixer The viscosity of some creams is such that they cannot be manufactured by a rotor/stator mixer alone. These can be processed with a Silverson Bottom Entry Mixer in conjunction with a stirrer/scraper unit as illustrated. Also suitable for products that increase in viscosity or solidify on cooling. The stirrer/scraper unit ensures that the output of the Silverson mixer is uniformly distributed throughout the vessel and prevents a localized heat build up on the walls of the jacketed vessel. Two-speed units available.Variable speed can be obtained with an inverter.

Advantages of the Silverson mixer Stable emulsion Agglomerate-free mix Dramatically reduced mixing time Maximized yield of raw materials as thickening agents are fully hydrated and other ingredients fully dispersed In-tank baffles are not required, improving vessel hygiene Pre-mixing of powdered ingredients can be eliminated The aqueous phase can be produced at ambient temperatures, reducing heating costs. This also accelerates cooling of the mixture, further reducing process time and costs Consistent product quality and repeatability

Production of Pharmaceutical Creams & Ointments Products can be either a water in oil (w/o) or oil in water (o/w) emulsion, consisting of waxes, emollients and lubricants dispersed in an oil phase, and a water phase containing emulsifying, stabilizing and thickening agents, preservatives and in some cases, colorant. Active ingredients are dispersed in either phase or added when the emulsion has been formed and allowed to cool.

Requirements to the ointment base: 1. they should have release ability - structural and mechanical properties are necessary for this aim; 2. they should have ability well-hold drugs - have absorb capacity; 3. they should are not changed under the influence of environmental conditions and do not react with drugs - possess chemical resistance;

Requirements to the ointment base: 4. they should be pharmacological indifferent, have not irritating and sensitizing effect; 5. they have be resistant to microbial contamination; 6. they should have property for conform use of the ointment.

Attributes of the ointments quality: 1. Description 2. Identification of medicine substances 3. Quantitative of MS 4. The particles size 5. pH 6. Microbiological purity 7. Quantity of acid and peroxide 8. Impurities 9. Sterility 10. Tightness of the container