Ansels Pharmaceutical Dosage Forms And Drug Delivery System Nineth Edition 

Ansels Pharmaceutical Dosage Forms And Drug Delivery System Nineth Edition pdf free download


The purpose of this text is to introduce pharmacy students to the principles, practices, and technologies applied in the preparation of pharmaceutical dosage forms and drug delivery systems. An integrated presentation is used in this teJ1.tbook to demonstrate the inter relationships between phan11aceutical and biopharmaceutical principles, product design, formulation, manufacture, compounding, and the clinical application of the various dosage forms in patient care. Regulations and standards governing the manufacturing and compounding of pharmaceuticals are also presented.

As has been the hallmark of this textbook since its first edition more than 40 years ago, each chapter is written at a level consistent with the requirements of students being introduced to this area of study. Because this textbook often is used early in the professional curriculum, it contains important intro­ductory topics, such as the historical development of drugs and pharmacy, the role of the pharmacist in contemporize practice, standards of the United States Pharmacopeia-National Formulary, systems and techniques of pharmaceutical measurement, pharmaceutical and biopharmaceutical principles applicable to drug product development, current good manufacturing practice and current good com­pounding practice standards, and the regulatory process by which pharmaceuticals are approved for marketing by the federal Food and Drug Administration.

The detailed presentation of each dosage form includes physical, physicochemical, and clinical discussions. The new activities at the end of each chapter are designed to provide opportunities for creative thought and application of the content.

INTRODUCTION TO DRUGS, DRUG DOSAGE FORMS, AND DRUG DELIVERY SYSTEMS

A drug is defi ned as an agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or in other  animals (Food, Drug, and Cosmetic Act, 1938). One of the most astounding qualities of drugs is the diversity of their actions and effects on the body. This quality enables their selective use in the treatment of a range of common and rare conditions involving virtually every body organ, tissue, and cell.

Some drugs selectively stimulate the cardiac muscle, the central nervous system, or the gas-trointestinal tract, whereas other drugs have the opposite effect. Mydriatic drugs dilate the pupil of the eye, and miotics constrict or diminish pupillary size. Drugs can render blood more coagulable or less coagulable; they can increase the hemoglobin content of the erythrocytes, reduce serum cholesterol, or expand blood  volume.

Drugs termed emetics induce vomiting, whereas antiemetic drugs prevent vomiting.  Diuretic drugs increase the fl ow of urine;  expectorant drugs increase respiratory tract fl uid; and cathartics or laxatives evacuate the bowel. Other drugs decrease the fl ow of urine, diminish body secretions, or induce constipation.

Drugs may be used to reduce pain, fever, thyroid activity, rhinitis, insomnia, gastric acid-ity, motion sickness, blood pressure, and men-tal depression. Other drugs can elevate mood, blood pressure, or activity of the  endocrine glands. Drugs can combat  infectious disease, destroy intestinal worms, or act as antidotes against the poisoning effects of other drugs. Drugs can assist in smoking cessation or alco-hol withdrawal or can modify obsessive– compulsive disorders.

Drugs are used to treat common infections, AIDS, benign prostatic hyperplasia, cancer, car-diovascular disease, asthma, glaucoma, Alzheimer disease, and male impotence. They can  protect against the rejection of transplanted tissues and organs and reduce the incidence of measles and mumps. Antineoplastic drugs provide one means of attacking the cancerous  process; radioactive pharmaceuticals provide another. Drugs may be used to diagnose diabetes, liver malfunction, tuberculosis, or pregnancy. They can replenish a body defi cient in antibodies, vitamins, hormones, electrolytes, protein, enzymes, or blood. Drugs can prevent pregnancy, assist fertility, and sus-tain life itself.

Certainly, the vast array of effective medicinal agents available today is one of our greatest scientifi c accomplishments. It is diffi cult to con-ceive our civilization devoid of these remarkable and benefi cial agents. Through their use, many of the diseases that have plagued humans through-out history, such as smallpox and poliomyelitis, are now virtually extinct. Illnesses such as diabe-tes, hypertension, and mental depression are effectively controlled with modern drugs. Today’s surgical procedures would be  virtually impossible without the benefi t of anesthetics, analgesics, antibiotics, blood transfusions, and intravenous fl uids.

New drugs may be derived from plant or  animal sources, as by-products of microbial growth, or through chemical synthesis, molecu-lar modifi cation, or biotechnology. Computer libraries and data banks of chemical compounds and sophisticated methods of screening for potential biologic activity assist drug discovery.

The process of drug discovery and develop-ment is complex. It entails the collective contri-butions of many scientifi c specialists, including organic, physical, and analytical chemists; bio-chemists; molecular biologists; bacteriologists; physiologists; pharmacologists; toxicologists; hematologists; immunologists; endocrinologists; pathologists; biostatisticians; pharmaceutical  scientists; clinical pharmacists; physicians; and many others.

After a potential new drug substance is dis-covered and undergoes defi nitive chemical and physical characterization, a great deal of biologic information must be gathered. The basic phar-macology, or the nature and mechanism of action of the drug on the biologic system, must be determined including toxicologic features. The drug’s site and rate of absorption, its pattern of  distribution and concentration within the body, its duration of action, and the method and rate of its elimination or excretion must be stud-ied. Information on the drug’s metabolic degra-dation and the activity of any of its metabolites must be obtained. A comprehensive study of the  short-term and long-term effects of the drug on various body cells, tissues, and organs must be made. Highly specifi c information, such as the effect of the drug on the fetus of a pregnant  animal or its ability to pass to a nursing baby through the breast milk of its mother, may be obtained. Many a promising new drug has been abandoned because of its potential to cause excessive or  hazardous adverse effects.

The most effective routes of administration (e.g., oral, rectal, parenteral, topical) must be determined, and guidelines for the dosages rec-ommended for persons of varying ages (e.g., neo-nates, children, adults, geriatrics), weights, and states of illness have to be established. It has been said that the only difference between a drug and a poison is the dose. To facilitate  administration of the drug by the selected routes, appropriate dosage forms, such as tablets, cap-sules, injections, suppositories, ointments, aero-sols, and others, are formulated and prepared. Each of these dosage units is designed to contain a specifi ed quantity of medication for ease and accuracy of dosage administration. These dosage forms are highly sophisticated delivery systems. Their design, development, production, and use are the product of application of the pharma-ceutical sciences—the blending of the basic, applied, and clinical sciences with pharmaceuti-cal  technology.

Each particular pharmaceutical product is a formulation unique unto itself. In addition to the active therapeutic ingredients, a pharmaceutical formulation contains a number of nontherapeu-tic or pharmaceutical ingredients. It is through their use that a formulation achieves its unique composition and characteristic physical appear-ance. Pharmaceutical ingredients include such materials as fi llers, thickeners, solvents, suspen-ding agents, tablet coatings and disintegrants, penetration enhancers, stabilizing agents, anti-microbial preservatives, fl avors, colorants, and sweeteners.

To ensure the stability of a drug in a formula-tion and the continued effectiveness of the drug product throughout its usual shelf life, the prin-ciples of chemistry, physical pharmacy, microbi-ology, and pharmaceutical technology must be applied. The formulation must be such that all components are physically and chemically  compatible, including the active therapeutic agents, the pharmaceutical ingredients, and the  packaging materials. The formulation must be  preserved against decomposition due to chemi-cal degradation and protected from microbial contamination and the destructive infl uences of excessive heat, light, and moisture. The thera-peutic ingredients must be released from the dosage form in the proper quantity and in such a manner that the onset and duration of the drug’s action are that which are desired. The pharma-ceutical product must lend itself to effi cient administration and must possess attractive  features of fl avor, odor, color, and texture that enhance acceptance by the patient. Finally, the product must be effectively packaged and clearly and completely labeled according to legal  regulations.

Once prepared, the pharmaceutical product must be properly administered if the patient is to receive maximum benefi t. The medication must be taken in suffi cient quantity, at specifi ed inter-vals, and for an indicated duration to achieve the desired therapeutic outcomes. The effectiveness of the medication in achieving the prescriber’s objectives should be reevaluated at regular inter-vals and necessary adjustments made in the dos-age, regimen, schedule, or form, or indeed, in the choice of the drug administered. Patients’ expressions of disappointment in the rate of progress or complaints of side effects to the pre-scribed drug should be evaluated and decisions made as to the continuance, adjustment, or major change in drug therapy. Before initially taking a medication, a patient should be advised of any expected side effects and of foods, bever-ages, and/or other drugs that may interfere with the effectiveness of the medication.

Through professional interaction and com-munication with other health professionals, the pharmacist can contribute greatly to patient care. An intimate knowledge of drug actions, pharma-cotherapeutics, formulation and dosage form design, available pharmaceutical products, and drug information sources makes the pharmacist a vital member of the health care team. The pharmacist is entrusted with the legal responsi-bility for the procurement, storage,  control, and distribution of effective pharmaceutical products and for the compounding and fi lling of prescrip-tion orders. Drawing on extensive training and knowledge, the pharmacist serves the patient as an advisor on drugs and encourages their safe and proper use through patient counseling. The pharmacist delivers pharmaceutical services in a variety of  community and institutional health care environments and effectively uses medica-tion records, patient monitoring, and assessment techniques in safeguarding the public health.

To appreciate the progress that has been made in drug discovery and development and to provide background for the study of modern drugs and pharmaceutical dosage forms, it is important to examine pharmacy’s heritage.

DRUG DOSAGE FORM AND DRUG DELIVERY SYSTEM DESIGN

Drug substances are seldom administered alone; rather they are given as part of a formulation in combination with one or more nonmedicinal agents that serve varied and specialized pharma-ceutical functions. Selective use of these nonme-dicinal agents, referred to as pharmaceutical ingredients or excipients, produces dosage forms of various types. The pharmaceutical ingredients solubilize, suspend, thicken, dilute, emulsify, sta-bilize, preserve, color, fl avor, and fashion medici-nal agents into effi cacious and appealing dosage forms. Each type of dosage form is unique in its physical and pharmaceutical characteristics. These varied preparations provide the manufac-turing and compounding pharmacist with the challenges of formulation and the physician with the choice of drug and delivery system to  prescribe. The general area of study concerned with the formulation, manufacture, stability, and effectiveness of pharmaceutical dosage forms is termed pharmaceutics.
The proper design and formulation of a  dosage form requires consideration of the physi-cal, chemical, and biologic characteristics of all of the drug substances and pharmaceutical ingredients to be used in fabricating the prod-uct. The drug and pharmaceutical materials must be compatible with one another to produce a drug product that is stable, effi cacious, attrac-tive, easy to administer, and safe. The product should be manufactured with appropriate mea-sures of quality control and packaged in contain-ers that keep the product stable. The product should be labeled to promote correct use and be stored under conditions that contribute to maxi-mum shelf life.
Methods for the preparation of specifi c types of dosage forms and drug delivery systems are described in subsequent chapters. This chapter presents some general considerations regarding physical pharmacy, drug product formulation, and pharmaceutical ingredients

SOLID DOSAGE FORMS AND SOLID MODIFIED-RELEASE DRUG DELIVERY SYSTEMS


Most active and inactive pharmaceutical  ingredients occur in the solid state as amorphous  powders or as crystals of various morphologic structures. The term “powder” has more than one connotation in pharmacy. It may be used to describe the physical form of a material, that is, a dry substance composed of fi nely divided par-ticles. Or, it may be used to describe a type of pharmaceutical preparation, that is, a medicated powder intended for internal (i.e., oral powder) or external (i.e., topical powder) use. Powders are intimate mixtures of dry, fi nely divided drugs and/or chemicals that may be intended for inter-nal or external use.
Although the use of medicated powders per se in therapeutics is limited, the use of powdered substances in the preparation of other dosage forms is extensive. For example, powdered drugs may be blended with powdered fi llers and other pharmaceutical ingredients to fabricate solid dosage forms as tablets and capsules; they may be dissolved or suspended in solvents or liquid vehi-cles to make various liquid dosage forms; or they may be incorporated into semisolid bases in the preparation of medicated ointments and creams.
Granules, which are prepared agglomerates of powdered materials, may be used per se for the medicinal value of their content, or they may be used for pharmaceutical purposes, as in  making tablets, as described later in this and Chapters 7 and 8.

SEMISOLID DOSAGE FORMS AND TRANSDERMAL SYSTEMS


Ointments, creams, 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 con-tain. The unmedicated ones are used for their physical effects as protectants or lubricants.
Topical preparations are used for both local and systemic effects. Systemic drug absorption should always be considered when using topical products if the patient is pregnant or nursing, because drugs can enter the fetal blood supply and breast milk and be transferred to the fetus or nursing infant.
Topical applications can be designed for either local effects or systemic absorption. The following distinction is an important one with regard to dermatologic applications. A topical  dermatological product is designed to deliver drug into the skin in treating dermal disorders, with the skin as the target organ. A transdermal product is designed to deliver drugs through the skin (percutaneous absorption) to the general circulation for systemic effects, with the skin not being the target organ (1).

LIQUID DOSAGE FORMS


In physicochemical terms, solutions may be  prepared from any combination of solid, liquid, and gas, the three states of matter. For example, a solid solute may be dissolved in another solid, a liquid, or a gas, and the same being true for a liquid solute and for a gas, nine types of homogeneous mixtures are possible. In pharmacy, how-ever, interest in solutions is for the most part limited to preparations of a solid, a liquid, and less frequently a gas solute in a liquid solvent.
In pharmaceutical terms, solutions are “liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents” (1). Because of a particular pharmaceutical solution’s use, it may be classified as oral, otic, ophthalmic, or topical. Still other solutions, because of their composition or use, may be classifi ed as other dosage forms. For example, aqueous solutions containing a sugar are classified as syrups (even though some syrups may contain some alcohol), sweetened hydroalcoholic (combinations of water and ethanol) solutions are termed elixirs, and solu-tions of aromatic materials are termed spirits if the solvent is alcoholic or aromatic waters if the solvent is aqueous. Solutions prepared by extract-ing active constituents from crude drugs are termed tinctures or fl uidextracts, depending on their method of preparation and concentration. Tinctures may also be solutions of chemical sub-stances dissolved in alcohol or in a hydroalcoholic solvent. Certain solutions prepared to be sterile and pyrogen free and intended for parenteral administration are classifi ed as injections. Although other examples could be cited, it is apparent that a solution, as a distinct type of pharmaceutical preparation, is much further defi ned than the physicochemical defi nition of the term solution.
Oral solutions, syrups, elixirs, spirits, and tinc-tures are prepared and used for the specifi c effects of the medicinal agents they carry. In these preparations, the medicinal agents are intended to provide systemic effects. The fact that they are administered in solution form  usually means that they are soluble in aqueous systems and their absorption from the gastrointestinal tract into the systemic circulation may be expected to occur more rapidly than from  suspension or solid dosage forms of the same medicinal agent.
Solutes other than the medicinal agent are usually present in orally administered solutions. These additional agents are frequently included to provide color, fl avor, sweetness, or stability. In formulating or compounding a pharmaceutical solution, the pharmacist must use information on the solubility and stability of each solute with regard to the solvent or solvent system. Combinations of medicinal or pharmaceutical agents that will result in chemical and/or physical inter-actions affecting the therapeutic quality or pharmaceutical stability of the product must be avoided.
For single-solute solutions and especially for multiple-solute solutions, the pharmacist must be aware of the solubility characteristics of the solutes and the features of the common pharmaceutical solvents. Each chemical agent has its own solubility in a given solvent. For many medicinal agents, their solubilities in the usual solvents are stated in the United States Pharmacopeia National Formulary (USP–NF) as well as in other reference books.

STERILE DOSAGE FORMS AND DELIVERY SYSTEMS

Considered in this chapter are important  pharmaceutical dosage forms with the common characteristic of sterility; that is, they are free from contaminating microorganisms. Among these sterile dosage forms are the various small- and large-volume injectable preparations, irrigation fluids intended to bathe body wounds or surgical openings, and dialysis solutions. Biologic preparations, including vaccines, toxoids, and antitoxins, also among this group are discussed in Chapter 16. Sterility in these preparations is essential because they are placed in direct con-tact with the internal body fluids or tissues, where infection can easily arise. Ophthalmic preparations, which are also prepared to be  sterile, are discussed separately in Chapter 17.

  

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