STAGES OF PHARMACEUTICAL MANUFACTURING

Transcription

1 STAGES OF PHARMACEUTICAL MANUFACTURING API Finished Product API Primary Packaging Secondary Packaging Excipients Starting Materials (Chemicals) 1

2 PHARMACEUTICAL MANUFACTURING OF NORMAL DOSAGE FORMS 2

3 Dosage Forms Tablets/Capsules Injectables Inhalants Transdermal products and implants Drug Skin ages/c_rx-capsule.jpg njectable.jpg pr/releases/images/vec tura-inhale.gif pg 3

4 1. SOLID DOSAGE FORMS Oral Tablets Lozenges Chewable tablets Effervescent tablets Multi-layer tablets Modified release Capsules Hard gelatin Soft gelatin Powders Inhaled Aerosol Metered dose inhalers Dry powder inhalers 4

5 Drug substances are most frequently administered as solid dosage formulations, mainly by the oral route. Tablets and capsules are the most frequently used solid dosage forms, have been in existence since the nineteenth century, and are unit dosage forms, comprising a mixture of ingredients presented in a single rigid entity, usually containing an accurate dose of a drug. There are other types of solid dosage forms designed to fulfill specific delivery requirements, but they are generally intended for oral administration and for systemic delivery. The major solid oral dosage form is the tablet, and these can range from relatively simple, single, immediate release dosage forms to complex modified - release systems. Tablets offer advantages for both patients and manufacturers 5

6 ADVANTAGES OF TABLETS AS A DOSAGE FORM 6

7 Tablets are classified by their route of administration or their function, form, or manufacturing process. For example, some tablets are designed to be placed in the oral cavity and to dissolve there or to be chewed before swallowing, and there are many kinds of formulation designed for sustained or controlled release 7

8 Dissolution of the drug must occur before or on reaching the absorption site before absorption can occur, and generally water - soluble drugs do not exhibit formulation difficulties. For poorly water - soluble drugs, the absorption rate may be dictated by the dissolution rate, and, if dissolution is slow, bioavailability may be compromised. The solubility of a drug should, therefore, be considered along with its dose when designing formulations, and unsuitable biopharmaceutical properties is the major reason for the failure of new drugs. According to the Biopharmaceutics Classification System (BCS), drug substances are classified as follows : Class I: high permeability, high solubility Class II: high permeability, lowsolubility Class III: low permeability, high solubility Class IV: low permeability, lowsolubility 8

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10 EXCIPIENTS IN SOLID DOSE FORMULATIONS In addition to the active ingredients, solid oral dosage forms will also contain a range of substances called excipients. The role of excipients is essential in ensuring that the manufacturing process is successful and that the quality of the resultant formulation can be guaranteed. The appropriate selection of excipients and their relative concentrations in the formulation is critical in development of a successful product. Although they are often categorized as inert, preformulation studies can determine the influence of excipients on stability, bioavailability, and processability. Excipients are categorized into groups according to their main function 10

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12 1.1. COATED TABLETS Tablets are often coated to protect the drug from the external environment, to mask bitter tastes, add mechanical strength, or to enhance ease of swallowing. A coating can also be used for aesthetic or commercial purposes, improving product appearance and identity. a) Sugar Coated Tablets b) Film Coated Tablets c) Compression Coating and Layered Tablets d) Tablet Wrapping 12

13 1.2. HARD AND SOFT GELATIN CAPSULES 13

14 Capsules are solid oral dosage forms in which the drug is enclosed within a hard or soft shell. The shell is normally made from gelatin and results in a simple, easy - to swallow formulation with no requirement for a further coating step. They can be either hard or soft depending on the nature of the capsule shell, with soft capsules possessing a flexible, plasticized gelatin film. Hard gelatin capsules are usually rigid two - piece capsules that are manufactured in one procedure and packed in another totally separate operation, whereas the formulation of soft gelatin capsules is more complex but all steps are integrated. 14

15 Liquid Excipients Compatible with Hard Gelatin Capsules 15

16 1.3. EFFERVESCENT TABLETS 16

17 Effervescence is the reaction in water of acids and bases to produce carbon dioxide, and effervescent tablets are dissolved or dispersed in water before administration. Advantages of effervescent formulations over conventional formulations are that the drug is usually already in solution prior to ingestion and can therefore have a faster onset of action. Although the solution may become diluted in the GI tract, any precipitation should be as fi ne particles that can be readily redissolved. Variability in absorption can also be reduced. Formulations can be made more palatable and there can be improved tolerance after ingestion. Thus, the types of drugs suited to this formulation method are those that are difficult to digest or are irritant to mucosa. Analgesics such as paracetamol and aspirin and vitamins are common effervescent formulations. The inclusion of buffering agents can aid stability of ph sensitive drugs. There is also the opportunity to extend market share and to deliver large doses of medication. 17

18 1.4. CHEWABLE TABLETS Chewable tablets are designed to be mechanically disintegrated in the mouth. Potential advantages of chewable tablets are mainly concerning patient convenience and acceptance, although enhanced bioavailability is also claimed. 18

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21 2. SEMI-SOLID DOSAGE FORMS Ointments, creams, paste and gels are semisolid dosage forms intended for topical application. They may be applied to the skin, placed on the surface of the eye, or used nasally, vaginally, or rectally. Most of these preparations are used for the effects of the therapeutic agents they contain. The un-medicated ones are used for their physical effects as protectants or lubricants. Topical preparations are used for both local and systemic effects. 21

22 PHARMACEUTICAL OINTMENTS AND PASTES Pharmaceutical ointments are semisolid systems that are applied externally, primarily to the skin and also to mucous membranes, e.g. The rectum, the vagina/vulva, the eye. Typically, medicated ointments are used for the treatment of infection, inflammation and pruritus. However, non-medicated ointments are commonly used due to their emollient/lubricating properties. Pharmaceutical pastes are generally composed of ointment bases that contain a high concentration (frequently 50% w/w) of dispersed drug. The viscosity of pharmaceutical pastes is greater than that of pharmaceutical ointments. 22

23 ADVANTAGES 1) Pharmaceutical ointments may be easily spread on skin, being retained at the site of application as an occlusive layer, thereby preventing moisture loss from the skin. This is particularly useful whenever restoration of the physical characteristics of the skin is required (e.g. due to inflammation). 2) Pharmaceutical ointments are associated with lubricating properties, properties that may be employed to reduce trauma of an affected site upon spreading. 3) In general, pharmaceutical ointments persist at the site of application, enabling the duration of drug release to be greater than for many other topical dosage forms. The increased viscosity of pharmaceutical pastes ensures that a thick film of the dosage form is applied to the site of action, which shows excellent persistence. This property is particularly useful if protection of an inflamed site is required, e.g. in eczema, psoriasis. 23

24 ADVANTAGES 4) The hydrophobicity and retention of pharmaceutical ointments are useful attributes whenever applied to mucosa, e.g. İnflamed haemorrhoids, eyelids, where fluid flow/inflammation at these sites would normally serve to remove other formulations (e.g. oil in water creams) by dilution. It should be noted, however, that spreading of ointments on to moist surfaces may be difficult due to the hydrophobic properties of most ointments. 24

25 DISADVANTAGES 1) Pharmaceutical ointments are generally greasy and difficult to remove (and are therefore often cosmetically unacceptable). Similarly, liniments and lotions may also be cosmetically unacceptable to the patient and difficult to use. 2) Pharmaceutical pastes are generally applied as a thick layer at the required site and are therefore considered to be cosmetically unacceptable. 3) Staining of clothes is often associated with the use of pharmaceutical pastes and ointments 4) The viscosity of pharmaceutical ointments, and in particular pastes, may be problematic in ensuring spreading of the dosage form over the affected site. Conversely, the low viscosity of liniments and lotions may result in application difficulties 25

26 DISADVANTAGES 5) Pharmaceutical ointments may not be applied to exuding sites however, please note that this does not hold for pastes.liniments may not be applied to broken skin. 6) Problems concerning drug release from pharmaceutical ointments may occur if the drug has limited solubility in the ointment base. 7) Pharmaceutical pastes are generally not applied to the hair due to difficulties associated with removal. 8) Therapeutic agents that are prone to hydrolysis should not be formulated into aqueous gels. 26

27 The formulation of ointments and pastes involves the dispersal or dissolution of the selected therapeutic agent into an ointment base and, therefore, in addition to the physical properties of the dispersed/dissolved drug, the physicochemical properties of the ointment base are fundamental to the clinical and non-clinical performance of this type of dosage form. The choice of ointment base is dependent on several factors, including: (1) the site of application; (2) the required rate of drug release; (3) the chemical stability of the drug; and (4) the effect of the therapeutic agent on formulation viscosity. 27

28 TYPES OF BASE There are four types of base that are used to formulate pharmaceutical ointments and pastes: (1) hydrocarbon; (2) absorption; (3) watermiscible/removable ; and (4) water-soluble. 28

29 (1) HYDROCARBON BASES Hydrocarbon bases (oleaginous bases) are water-free, and aqueous preparations may be incorporated into them only in small amounts and then with difficulty. Hydrocarbon bases are retained on the skin for prolonged periods, do not permit the escape of moisture from the skin to the atmosphere, and are difficult to wash off. As such they act as occlusive dressings. They do not "dry out" or change noticeably upon aging.

30 Petrolatum a mixture of semisolid hydrocarbons obtained from petroleum an unctuous mass, varying in color from yellow to white It may be used alone or in combination with other agents as an ointment base Commercial product is Vaseline

31 Paraffin A purified mixture of solid hydrocarbons obtained from petroleum. A colorless or white, more or less translucent mass that may be used to harden or stiffen oleaginous semisolid ointment bases.

32 Liquid paraffin a colorless, odorless oily liquid consisting of a mixture of hydrocarbons obtained from petroleum has the same character with paraffin be used in combination with paraffin to adjust viscosity

33 Hydrophilic Petrolatum is composed of cholesterol, stearyl alcohol, white wax, and white petrolatum has the ability to absorb water, with the formation of a water-in-oil emulsion. Aquaphor is a highly refined variation of Hydrophilic Petrolatum and because it can absorb up to 3 times its weight in water, it has proven useful to incorporate extemporaneously a water-soluble drug into an oleaginous base.

34 Anhydrous Lanolin (refined wool fat) may contain no more than 0.25% of water. insoluble in water, but mixes without separation with about twice its weight of water The incorporation of water results in the formation of a water-in-oil emulsion.

35 Lanolin (hydrous Wool Fat ) a semisolid, fatlike substance obtained from the wool of sheep. a water-in-oil emulsion that contains between 25 and 30% water. Additional water may be incorporated into lanolin by mixing.

36 Beeswax and spermaceti They are weak sufactants (W/O) and used as stabilization agents in O/W emulsive ointment.

37 MINERAL OIL a mixture of liquid hydrocarbons. It is useful as a levigating substance to wet and to incorporate solid substances into the preparation of ointments that consist of oleaginous bases as their vehicle.

38 2) ABSORPTION BASES Absorption bases may be of two types: those that permit the incorporation of aqueous solutions, resulting in the formation of water-in-oil emulsions (e.g. Hydrophilic Petrolatum and Anhydrous lanolin) and those that are already water-in-oil emulsions (emulsion bases) that permit the incorporation of small, additional quantities of aqueous solutions (e.g. lanolin and Cold Cream).

39 These bases are useful as emollients although they do not provide the degree of occlusion afforded by the oleaginous bases. Absorption bases are not easily removed from the skin with water washing. They are also useful pharmaceutically to incorporate aqueous solutions of drugs, e g., sodium sulfacetamide, into oleaginous bases.

40 3)WATER-REMOVABLE BASES oil-in-water emulsions that are capable of being washed from skin or clothing with water. For this reason, they are frequently referred to as "water-washable" ointment bases may be diluted with water or with aqueous solutions. have the ability to absorb serous discharges in dermatologic conditions. Certain medicinal agents may be better absorbed by the skin when present in a base of this type than in other types of bases.

41 Emulsifying agents sodium lauryl sulfate :O/W emulsion stearyl alcohol and cetyl alcohol representing the oleaginous phase of the W/O emulsion to improve the stabilization and viscosity. sodium stearate and calcium stearate. Glyceryl monostearate: weak W/O emulsifying agents and used as stabilization agents and emollient in the O/W emulsion.

42 Stearic acid, beewax and paraffin are the main oleaginous bases. propylene glycol and water representing the aqueous phase Methylparaben and propylparaben are used to preserve the ointment against microbial growth

43 4) WATER-SOLUBLE BASES contain only water-soluble components. are water washable Because they soften greatly with the addition of water, aqueous solutions are not effectively incorporated into these bases. Rather, they are better used for the incorporation of nonaqueous or solid substances.

44 SELECTION OF THE APPROPRIATE BASE 1. Desired release rate of the drug substance from the ointment base 2. Desirability of topical or percutaneous drug absorption 3. Desirability of occlusion of moisture from the stability of the drug in the ointment base 4. Effect, if any, of the drug on the consistency or other features of the ointment base 5. Desire for a base easily removed by washing with water 6. Characteristics of the surface to which it is applied for example, an ointment is generally applied to dry, scaly skin; a cream is applied to weeping or oozing surfaces; and a lotion is applied to intertriginous areas or where friction may occur, as between the thighs or under the armpit. The base that provides the best combination of the most desired attributes should be selected. 44

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51 Semisolid production machine with heat jacketed vessel, high - shear mixer, scrapper, vacuum attachments, and control station 51

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