Physiologic Characteristics Of The Gastrointestinal Tract

Published Date: 02 Nov 2017

Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms.

All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of the mode of delivery (Immediate, Extended or Controlled release) and the design of dosage forms (either solid, dispersion, or liquid), must be developed within the intrinsic characteristics of GI physiology.

The most sophisticated delivery system, the greater is the complexity of these various disciplines involved in the design and optimization of the system. In any case, the scientific framework required for the successful development of an oral drug delivery system consists of a basic understanding of the following three aspects:

The anatomic and physiologic characteristics of the gastrointestinal tract.

Physicochemical, pharmacokinetic and pharmacodynamic characteristics of the drug.

Physicomechanical characteristics and the drug delivery mode of the dosage form to be designed.

Table 1.1: Anatomic and physiologic characteristics of the gastrointestinal tract3

Region

Surface Area

(m2)

pH of The Region

Transit Time

Fluid

Solid

GIT

200

1-8

-

-

Stomach

0.1-0.2

1-3.5

50 min.

8 hrs.

Small intestine

4500

5-7.5

2-6 hrs.

4-9 hrs.

Large intestine

0.5-0.1

6.8

2-6 hrs.

3 hrs. to 3 days

Figure 1.1:-Gastrointestinal anatomy and dynamics

Stomach3

The stomach is an organ with a capacity for storage and mixing. Under fasting conditions the stomach is a collapsed bag with a residual volume of 50 mL and contains a small amount of gastric fluid (pH 1-3) and air. The stomach has four main areas: cardia, fundus, body, and pylorus. Within 2-4 hrs after eating a meal the stomach has emptied its contents into the duodenum.

Intestine3

The small intestine is a tubular viscous organ and has enormous number of villi on its mucosal surface that create a huge surface area (4500 m2 compared to only 0.1-0.2 m2 for the stomach). The surface of the mucous membrane of the small intestine possesses about 5 million villi, each about 0.5 to 1 mm long. These villi are minute fingerlike projections of the mucosa and have a length of 0.5-1.5 mm, depending upon the degree of distension the intestinal wall and the state of contraction of smooth muscle fibres in their own interiors. Absorption of material occurs by facilitate diffusion, osmosis, and active transport. The small intestine is the largest section of the digestive tube and it is arbitrarily divided in to three parts. Duodenum (20-30 cm), Jejunum (2-5 m) and the ileum (3-5 m). The duodenum has a pH of 5 to 6 and the lower ileum approaches a pH of 8.

1.1.1 What is tablet?4-6

Tablets are solid preparations each containing a single dose of one or more active substances and usually obtained by compressing uniform volumes of particles. Tablets are intended for oral administration. Some are swallowed whole, some after being chewed, some are dissolved or dispersed in water before being administered and some are retained in the mouth where the active substance is liberated.

The particles consist of one or more active substances with or without excipients such as diluents, binders, disintegrating agents, glidants, lubricants, substances capable of modifying the behavior of the preparation in the digestive tract, colouring matter authorized by the competent authority and flavouring substances.

1.1.2. Type and Classes of Tablets4-6

A. Oral tablets for ingestion

Compressed tablets

Multiple compressed tablets

Layered tablets

Compression-coated tablets

Repeat-action tablets

Delayed-action and enteric-coated tablets

Sugar and chocolate –coated tablets

Film coated tablets

Chewable tablets

B. Tablets Used In the Oral Cavity

Buccal tablets

Sublingual tablets

Troches and lozenges

Dental cones

C. Tablets administered by other routes

Implantation tablets

Vaginal tablets

D. Tablets used to prepare solutions

Effervescent tablets

Dispensing tablets

Hypodermic tablets

Tablet triturates

1.1.3. Extended Release Tablet7-15

Extended release is term used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.

Advantages

The frequency of drug administration is reduced.

Patient compliance can be improved, and drug administration can be made more convenient as well.

The blood level oscillation characteristic of multiple dosing of conventional dosage forms is reduced, because a more even blood level is maintained.

A less obvious advantage, implicit in the design of Extended release forms, is that the total amount of drug administered can be reduced, thus maximizing availability with a minimum dose.

In addition, better control of drug absorption can be attained, since the high blood level peaks that may be observed after administration of a dose of a high availability drug can be reduced by formulation in an extended action form.

The safety margin of high-potency drugs can be increased, and the incidence of both local and systemic adverse side effects can be reduced in sensitive patient.

Limitations

Administration of Extended release medication does not permit the prompt termination of therapy. Immediate changes in drug need during therapy, such as might be encountered if significant adverse effects are noted, can not be accommodated.

The physician has less flexibility in adjusting dosage regimens. This is fixed by the dosage form design.

Extended release forms are designed for the normal population i.e., on the basis of average drug biological half-life. Consequently, disease states that alter drug disposition, significant patient variation.

Economic factors must also be assessed, since more costly processes and equipment are involved in manufacturing of many Extended release forms.

One of the least complicated approaches to the manufacture of Extended release dosage forms involves the direct compression of blends of drug, retardant material, and additives to form a tablet in which drug is embedded in a matrix core of the retardant. Alternately, retardant drug blends may be granulated prior to compression. Examples of three classes of retardant material used to formulate matrix tablets. Each class demonstrating a different approach to the matrix concept represents in Table 2.

Table 1.2:- Types of Matrix for Extended Release7-15

Sr.

No.

Matrix Characteristic

Material

1

Insoluble, inert

Polyethylene,

Polyvinyl chloride

Ethylcellulose

2

Insoluble, erodible

Carnauba wax,

Castor wax

3

Hydrophilic

Methylcellulose

Hydroxypropylmethylcellulose

Hydroxyethylcellulose

4

Hydrophobic

Ethyl cellulose

Glyceryl Behenate

Insoluble, inert material containing matrix tablets are not useful for high milligram potency formulations in which the polymer content would be sufficient to form a matrix, or for highly water-insoluble drugs in which dissolution in the matrix would become rate-limiting. Tablets may be directly compressed from mixtures of drug and ground polymer.

Hydrophilic matrix former represents non-digestible materials that form gels in situ. Drug release is controlled by penetration of water through a gel layer produced by hydration of the polymer and diffusion of drug through the swollen, hydrated matrix, in addition to erosion of the gelled layer.

Matrix systems offer several Advantages7-15:

Easy to manufacture

Versatile, effective, low cost

Can be made to release high molecular weight compounds

Since the drug is dispersed in the matrix system, accidental leakage of the total drug component is less likely to occur, although occasionally, cracking of the matrix material can cause unwanted release.

Disadvantages of the matrix systems:

The remaining matrix must be removed after the drug has been released.

The drug release rate varies with the square root of time.

However, a substantial Extended effect can be produced through the use of very slow release rates, which in many applications are indistinguishable from zero order.

Mechanism of Extended Release7-15:

Diffusion.

Dissolution.

Bioerodible and combination diffusion and dissolution systems

A) Diffusion

Reservoir

Membraneee

Figure 1.2:- Diffusion control of drug release by water insoluble Polymer7-15

Here, the polymer is water insoluble, so important factor is solubility of Drug in the membrane and so gives rise to the driving force for diffusion.

Reservoir

Membrane

Pores produces by soluble portion of water soluble polymer.

Figure 1.3:- Diffusion control of drug release by a partially water soluble polymer7-15

Here, polymer is partially soluble in water or mixture of water soluble and Water insoluble polymer is used. The water soluble polymer then dissolves Out of the film, giving rise to small channels through which the drug can diffuse.

Matrix diffusion controlled drug delivery system 7-15

In this type of controlled drug delivery system, the drug reservoir results from the homogeneous dispersion of the drug particles in either a lipophilic or a hydrophilic polymer matrix.

Figure 1.3:- Matrix Diffusion Controlled Drug Delivery System7-15

Where,

Zone 1: Undissolved drug, glassy polymer.

Zone 2: Undissolved drug, gel layer.

Diffusion front

Swelling front

Erosion frontZone 3

Zone 2

Zone1

Figure 1.3:- Matrix Diffusion Controlled Drug Delivery System7-15

Gel layer thickness = Difference between erosion and swelling front position

The rate of drug release from the system is time dependent and is given by,

dQ/dt = (ACrDp/2t) 1/2

Where, dQ /dt is rate of drug release,

A is loading dose

Cr is drug solubility in polymer

T is the time

Dp is drug diffusivity in the polymer.

B) Dissolution

Reservoir

Membrane

Figure 1.5:- Dissolution control of drug release via thickness and Dissolution rate of the membrane barrier coat. 7-15:

By varying the coating thickness, or layering concentric sphere of coating material And Drug reservoir material, gives rise to different release times, Producing the repeat action dosage form.

Table 1.3:- Types and mechanisms of Extended release system

Types

Mechanism

Matrix

Diffusion through a matrix or membrane

Reservior/Membrane

Chemical reaction-erosion or cleavage

Osmotic pumps

Solvent activation

C) Bio-erodible and combination diffusion and dissolution systems8-16

Strictly speaking, therapeutic systems will never be dependent on dissolution or diffusion only. In practice, the dominant mechanism for release will overshadow other processes enough to allow classification as either dissolution rate-limited or diffusion-controlled release.

As a further complication these systems can combine diffusion and dissolution of both the drug and the matrix material. Drugs not only can diffuse out of the dosage form, as with some previously described matrix systems, but also the matrix itself undergoes a dissolution process. The complexity of the system arises from the fact that as the polymer dissolves the diffusional path length for the drug may change. This usually results in a moving boundary diffusion system. Zero-order release is possible only if surface erosion occurs and surface area does not change with time.

Swelling-controlled matrices exhibit a combination of both diffusion and dissolution mechanisms. Here the drug is dispersed in the polymer, but instead of an insoluble or non-erodible polymer, swelling of the polymer occurs. This allows for the entrance of water, which causes dissolution of the drug and diffusion out of the swollen matrix. In these systems the release rate is highly dependent on the polymer-swelling rate and drug solubility. This system usually minimizes burst effects, as rapid polymer swelling occurs before drug release.

With regards to swellable matrix systems, different models have been proposed to describe the diffusion, swelling and dissolution processes involved in the drug release mechanism. However the key element of the drug release mechanism is the forming of a gel layer around the matrix, capable of preventing matrix disintegration and further rapid water penetration. When a matrix that contains a swellable glassy polymer comes in contact with a solvent or swelling agent, there is an abrupt change from the glassy to the rubbery state, which is associated with the swelling process.

The individual polymer chains, originally in the unperturbed state absorb water so that their end-to-end distance and radius of gyration expand to a new solvated state. This is due to the lowering of the transition temperature of the polymer (Tg), which is controlled by the characteristic concentration of the swelling agent and depends on both temperature and thermodynamic interactions of the polymer–water system.

A sharp distinction between the glassy and rubbery regions is observed and the matrix increases in volume because of swelling. On a molecular basis, this phenomenon can activate a convective drug transport, thus increasing the reproducibility of the drug release. The result is an anomalous non-fickian transport of the drug, owing to the polymer-chain relaxation behind the swelling position. This, in turn, creates osmotic stresses and convective transport effects.

The gel strength is important in the matrix performance and is controlled by the concentration, viscosity and chemical structure of the rubbery polymer. This restricts the suitability of the hydrophilic polymers for preparation of swellable matrices. Polymers such as carboxymethylcellulose, hydroxypropyl cellulose or tragacanthgum, do not form the gel layer quickly. Consequently, they are not recommended as excipients to be used alone in swellable matrices.

1.1.4. Extended release drug delivery systems17-19

During the past few years, conventional dosage forms of drugs are rapidly being replaced by the new and the novel drug delivery systems. Amongst, these the controlled release/extended release dosage forms have become extremely popular in modern therapeutics. The basic rationale for extended release drug delivery is to alter the pharmacokinetics and pharmacodynamics of drugs by using novel drug delivery systems or by modifying the molecular structure or physiological parameters inherent in a selected route of administration.

It is desirable that the duration of drug action becomes more a design property of a rate controlled dosage form and less or not at all a property of the drug molecule's inherent kinetic properties. Thus, optimal design of a extended release system necessitates through understanding of the pharmacokinetics and pharmacodynamics of the drug.

When the drug is administered in a conventional dosage form, it results in a fluctuation of drug concentration at the site of action (peak and valley pattern) and therefore in systemic circulation and tissue compartment. Figure 1.2 shows the difference between the conventional and extended release dosage forms.

Extended release drug administration means not only prolongation of duration of drug delivery, similarly to the action in the extended and prolonged release, but the term also implies the predictability and reproducibility of drug release kinetics. The controlled release of drug substances and their effective transport to sites of action can be exploited to maximize the beneficial clinical response and to minimize the incidence of unbeneficial adverse reaction & side effect7.

Figure 1.5:- Plasma drug concentration Vs. time profile: (A) conventional delivery with multiple dosing (B) Extended delivery.

1.1.4.1. Classification of extended/controlled release system17.

Classification according to release pattern:

Types of Non-immediate Release Drug Delivery System (NRDDS)

The conventional dosage forms are immediate release type.

Non-immediate release delivery system may be divided into three categories:

Delayed release drug delivery systems:

Repeat action Drug Delivery System

Timed release DDS

Sustained release drug delivery systems

Controlled release DDS

Prolonged release DDS

Extended release dosage forms

It is defined as the one that allows at least a two fold reduction in the dosing frequency as compared to that of conventional dosage form.

a) Controlled Action:

In this type of dosage forms it provides a prolonged duration of drug release with predictability and reproducibility of drug release kinetics. In this case, the rate of drug absorption is equal to the rate of drug removal from body.

b) Sustained Action:

In this type of dosage forms, a sufficient amount of drug is initially made available to the body to case a desired pharmacological response. The remaining fraction is release periodically and is required to maintain the maximum initial pharmacological activity for some desirable period of time in excess of time expected from usual single dose.

c) Prolonged Action:

These types of dosage form are designed in such a way that it release the drug over an extended period during which pharmacological response is obtained but does not necessarily maintain the constant blood level.

d) Delayed release dosage forms:

It is defined as one that releases the drug at a time other than "immediately" after administration.

e) Site specific and receptor release:

The basic rationale for controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery system or by modifying the molecular structure and/or physiological parameters inherent in a selected route of administration3.

1.1.4.2. Criteria to be met by drug proposed to be formulated in extended release dosage forms18,19

Desirable half-life.

High therapeutic index

Small dose

Desirable absorption and solubility characteristics.

Desirable absorption window.

First past clearance.

Desirable half-life:

The half-life of a drug is an index of its residence time in the body. If the drug has a short half-life (less than 2 hours), the dosage form may contain prohibitively large quantity of the drug. On the other hand, drug with elimination half-life of eight hours or more are sufficiently extended in the body, when administered in conventional dosage from, and extended release drug delivery system is generally not necessary in such cases. Ideally, the drug should have half-life of three to four hours.

High therapeutic index:

Drugs with low therapeutic index are unsuitable for incorporation in extended release formulations. If the system fails in the body, dose dumping may occur, leading to fatalities eg.Digitoxin.

Small dose:

If the dose of a drug in the conventional dosage form is high, its suitability as a candidate for extended release is seriously undetermined. This is chiefly because the size of a unit dose extended release formulation would become too big, to administer without difficulty.

Desirable absorption and solubility characteristics:

Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into extended release formulations is therefore unrealistic and may reduce overall absorption efficiency.

Desirable absorption window:

Certain drugs when administered orally are absorbed only from a specific part of gastrointestinal tract. This part is referred to as the ‘absorption window’. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as extended release dosage form are unsuitable.

First pass clearance

As discussed earlier in disadvantages of extended delivery system, delivery of the drug to the body in desired concentrations is seriously hampered in case of drug undergoing extensive

hepatic first pass metabolism, when administered in extended release forms.

1.1.5. Introduction to Hypertention20-24

Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a chronic medical condition in which the blood pressure in the arteries is elevated. This requires the heart to work harder than normal to circulate blood through the blood vessels. Blood pressure is summarised by two measurements, systolic and diastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole). Normal blood pressure at rest is within the range of 100-140mmHg systolic (top reading) and 60-90mmHg diastolic (bottom reading). High blood pressure is said to be present if it is persistently at or above 140/90 mmHg.

Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90–95% of cases are categorized as "primary hypertension" which means high blood pressure with no obvious underlying medical cause. The remaining 5–10% of cases (secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart or endocrine system.

Hypertension is a major risk factor for stroke, myocardial infarction (heart attacks), heart failure, aneurysms of the arteries (e.g. aortic aneurysm), peripheral arterial disease and is a cause of chronic kidney disease. Even moderate elevation of arterial blood pressure is associated with a shortened life expectancy. Dietary and lifestyle changes can improve blood pressure control and decrease the risk of associated health complications, although drug treatment is often necessary in people for whom lifestyle changes prove ineffective or insufficient.

1.1.5.1. Signs and symptoms

Hypertension is rarely accompanied by any symptoms, and its identification is usually through screening, or when seeking healthcare for an unrelated problem. A proportion of people with high blood pressure report headaches (particularly at the back of the head and in the morning), as well as lightheadedness, vertigo, tinnitus (buzzing or hissing in the ears), altered vision or fainting episodes. These symptoms however are more likely to be related to associated anxiety than the high blood pressure itself.

On physical examination, hypertension may be suspected on the basis of the presence of hypertensive retinopathy detected by examination of the optic fundus found in the back of the eye using ophthalmoscopy. Classically, the severity of the hypertensive retinopathy changes is graded from grade I–IV, although the milder types may be difficult to distinguish from each other. Ophthalmoscopy findings may also give some indication as to how long a person has been hypertensive.

Secondary hypertension

Some additional signs and symptoms may suggest secondary hypertension, i.e. hypertension due to an identifiable cause such as kidney diseases or endocrine diseases. For example, truncal obesity, glucose intolerance, moon facies, a "buffalo hump" and purple striae suggest Cushing's syndrome. Thyroid disease and acromegaly can also cause hypertension and have characteristic symptoms and signs. An abdominal bruit may be an indicator of renal artery stenosis (a narrowing of the arteries supplying the kidneys), while decreased blood pressure in the lower extremities and/or delayed or absent femoral arterial pulses may indicate aortic coarctation (a narrowing of the aorta shortly after it leaves the heart). Labile or paroxysmal hypertension accompanied by headache, palpitations, pallor, and perspiration should prompt suspicions of pheochromocytoma. A proportion of resistant hypertension appears to be the result of chronic high activity of the autonomic nervous system; this concept is known as "neurogenic hypertension".

Hypertensive crisis

Severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 110 — sometime termed malignant or accelerated hypertension) is referred to as a "hypertensive crisis", as blood pressures above these levels are known to confer a high risk of complications. People with blood pressures in this range may have no symptoms, but are more likely to report headaches (22% of cases) and dizziness than the general population. Other symptoms accompanying a hypertensive crisis may include visual deterioration or breathlessness due to heart failure or a general feeling of malaise due to renal failure. Most people with a hypertensive crisis are known to have elevated blood pressure, but additional triggers may have led to a sudden rise.

A "hypertensive emergency", previously "malignant hypertension", is diagnosed when there is evidence of direct damage to one or more organs as a result of the severely elevated blood pressure. This may include hypertensive encephalopathy, caused by brain swelling and dysfunction, and characterized by headaches and an altered level of consciousness (confusion or drowsiness). Retinal papilloedema and/or fundal hemorrhages and exudates are another sign of target organ damage. Chest pain may indicate heart muscle damage (which may progress to myocardial infarction) or sometimes aortic dissection, the tearing of the inner wall of the aorta. Breathlessness, cough, and the expectoration of blood-stained sputum are characteristic signs of pulmonary edema, the swelling of lung tissue due to left ventricular failure an inability of the left ventricle of the heart to adequately pump blood from the lungs into the arterial system. Rapid deterioration of kidney function (acute kidney injury) and microangiopathic hemolytic anemia (destruction of blood cells) may also occur. In these situations, rapid reduction of the blood pressure is mandated to stop ongoing organ damage. In contrast there is no evidence that blood pressure needs to be lowered rapidly in hypertensive urgencies where there is no evidence of target organ damage and over aggressive reduction of blood pressure is not without risks. Use of oral medications to lower the BP gradually over 24 to 48 h is advocated in hypertensive urgencies.

In pregnancy

Hypertension occurs in approximately 8–10% of pregnancies. Most women with hypertension in pregnancy have pre-existing primary hypertension, but high blood pressure in pregnancy may be the first sign of pre-eclampsia, a serious condition of the second half of pregnancy and puerperium. Pre-eclampsia is characterised by increased blood pressure and the presence of protein in the urine. It occurs in about 5% of pregnancies and is responsible for approximately 16% of all maternal deaths globally. Pre-eclampsia also doubles the risk of perinatal mortality. Usually there are no symptoms in pre-eclampsia and it is detected by routine screening. When symptoms of pre-eclampsia occur the most common are headache, visual disturbance (often "flashing lights"), vomiting, epigastric pain, and edema. Pre-eclampsia can occasionally progress to a life-threatening condition called eclampsia, which is a hypertensive emergency and has several serious complications including vision loss, cerebral edema, seizures or convulsions, renal failure, pulmonary edema, and disseminated intravascular coagulation (a blood clotting disorder).

In infants and children

Failure to thrive, seizures, irritability, lack of energy, and difficulty breathing can be associated with hypertension in neonates and young infants. In older infants and children, hypertension can cause headache, unexplained irritability, fatigue, failure to thrive, blurred vision, nosebleeds, and facial paralysis.

1.1.5.2. Cause

Primary hypertension

Primary (essential) hypertension is the most common form of hypertension, accounting for 90–95% of all cases of hypertension. In almost all contemporary societies, blood pressure rises with aging and the risk of becoming hypertensive in later life is considerable. Hypertension results from a complex interaction of genes and environmental factors. Numerous common genetic variants with small effects on blood pressure have been identified as well as some rare genetic variants with large effects on blood pressure but the genetic basis of hypertension is still poorly understood. Several environmental factors influence blood pressure. Lifestyle factors that lower blood pressure include reduced dietary salt intake, increased consumption of fruits and low fat products (Dietary Approaches to Stop Hypertension (DASH diet)), exercise, weight loss and reduced alcohol intake. Stress appears to play a minor role with specific relaxation techniques not supported by the evidence. The possible role of other factors such as caffeine consumption, and vitamin D deficiency are less clear cut. Insulin resistance, which is common in obesity and is a component of syndrome X (or the metabolic syndrome), is also thought to contribute to hypertension. Recent studies have also implicated events in early life (for example low birth weight, maternal smoking and lack of breast feeding) as risk factors for adult essential hypertension, although the mechanisms linking these exposures to adult hypertension remain obscure.

Secondary hypertension

Secondary hypertension results from an identifiable cause. Renal disease is the most common secondary cause of hypertension. Hypertension can also be caused by endocrine conditions, such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or hyperaldosteronism, hyperparathyroidism and pheochromocytoma. Other causes of secondary hypertension include obesity, sleep apnea, pregnancy, coarctation of the aorta, excessive liquorice consumption and certain prescription medicines, herbal remedies and illegal drugs.

1.1.5.3. Pathophysiology

In most people with established essential (primary) hypertension, increased resistance to blood flow (total peripheral resistance) accounting for the high pressure while cardiac output remains normal. There is evidence that some younger people with prehypertension or 'borderline hypertension' have high cardiac output, an elevated heart rate and normal peripheral resistance, termed hyperkinetic borderline hypertension. These individuals develop the typical features of established essential hypertension in later life as their cardiac output falls and peripheral resistance rises with age. Whether this pattern is typical of all people who ultimately develop hypertension is disputed. The increased peripheral resistance in established hypertension is mainly attributable to structural narrowing of small arteries and arterioles, although a reduction in the number or density of capillaries may also contribute. Hypertension is also associated with decreased peripheral venous compliance which may increase venous return, increase cardiac preload and, ultimately, cause diastolic dysfunction. Whether increased active vasoconstriction plays a role in established essential hypertension is unclear.

Pulse pressure (the difference between systolic and diastolic blood pressure) is frequently increased in older people with hypertension. This can mean that systolic pressure is abnormally high, but diastolic pressure may be normal or low — a condition termed isolated systolic hypertension. The high pulse pressure in elderly people with hypertension or isolated systolic hypertension is explained by increased arterial stiffness, which typically accompanies aging and may be exacerbated by high blood pressure.

Many mechanisms have been proposed to account for the rise in peripheral resistance in hypertension. Most evidence implicates either disturbances in renal salt and water handling (particularly abnormalities in the intrarenal renin-angiotensin system) and/or abnormalities of the sympathetic nervous system. These mechanisms are not mutually exclusive and it is likely that both contribute to some extent in most cases of essential hypertension. It has also been suggested that endothelial dysfunction and vascular inflammation may also contribute to increased peripheral resistance and vascular damage in hypertension.

1.1.5.4. Diagnosis

Hypertension is diagnosed on the basis of a persistently high blood pressure. Traditionally, this requires three separate sphygmomanometer measurements at one monthly intervals. Initial assessment of the hypertensive people should include a complete history and physical examination. With the availability of 24-hour ambulatory blood pressure monitors and home blood pressure machines, the importance of not wrongly diagnosing those who have white coat hypertension has led to a change in protocols. In the United Kingdom, current best practice is to follow up a single raised clinic reading with ambulatory measurement, or less ideally with home blood pressure monitoring over the course of 7 days. Pseudohypertension in the elderly or noncompressibility artery syndrome may also require consideration. This condition is believed to be due to calcification of the arteries resulting an abnormally high blood pressure readings with a blood pressure cuff while intra arterial measurements of blood pressure are normal.

Once the diagnosis of hypertension has been made, physicians will attempt to identify the underlying cause based on risk factors and other symptoms, if present. Secondary hypertension is more common in preadolescent children, with most cases caused by renal disease. Primary or essential hypertension is more common in adolescents and has multiple risk factors, including obesity and a family history of hypertension. Laboratory tests can also be performed to identify possible causes of secondary hypertension, and to determine whether hypertension has caused damage to the heart, eyes, and kidneys

Serum creatinine is measured to assess for the presence of kidney disease, which can be either the cause or the result of hypertension. Serum creatinine alone may overestimate glomerular filtration rate and recent guidelines advocate the use of predictive equations such as the Modification of Diet in Renal Disease (MDRD) formula to estimate glomerular filtration rate (eGFR). eGFR can also provides a baseline measurement of kidney function that can be used to monitor for side effects of certain antihypertensive drugs on kidney function. Additionally, testing of urine samples for protein is used as a secondary indicator of kidney disease. Electrocardiogram (EKG/ECG) testing is done to check for evidence that the heart is under strain from high blood pressure.

Table 1.4:- Classification of Hypertention

Classification

Systolic pressure

Diastolic pressure

mmHg

kPa

MmHg

kPa

Normal

90–119

12–15.9

60–79

8.0–10.5

Prehypertention

120–139

16.0–18.5

80–89

10.7–11.9

Stage 1 Hypertention

140–159

18.7–21.2

90–99

12.0–13.2

Stage 2 Hypertention

≥160

≥21.3

≥100

≥13.3

Isolated Systolic Hypertention

≥140

≥18.7

<90

<12.0

Adult

In people aged 18 years or older hypertension is defined as a systolic and/or a diastolic blood pressure measurement consistently higher than an accepted normal value (currently 139 mmHg systolic, 89 mmHg diastolic: see table —Classification (JNC7)). Lower thresholds are used (135 mmHg systolic or 85 mmHg diastolic) if measurements are derived from 24-hour ambulatory or home monitoring. Recent international hypertension guidelines have also created categories below the hypertensive range to indicate a continuum of risk with higher blood pressures in the normal range. JNC7 (2003) uses the term prehypertension for blood pressure in the range 120-139 mmHg systolic and/or 80-89 mmHg diastolic, while ESH-ESC Guidelines (2007) and BHS IV (2004) use optimal, normal and high normal categories to subdivide pressures below 140 mmHg systolic and 90 mmHg diastolic. Hypertension is also sub-classified: JNC7 distinguishes hypertension stage I, hypertension stage II, and isolated systolic hypertension. Isolated systolic hypertension refers to elevated systolic pressure with normal diastolic pressure and is common in the elderly. The ESH-ESC Guidelines (2007) and BHS IV (2004), additionally define a third stage (stage III hypertension) for people with systolic blood pressure exceeding 179 mmHg or a diastolic pressure over 109 mmHg. Hypertension is classified as "resistant" if medications do not reduce blood pressure to normal levels.

Children

Hypertension in neonates is rare, occurring in around 0.2 to 3% of neonates, and blood pressure is not measured routinely in the healthy newborn. Hypertension is more common in high risk newborns. A variety of factors, such as gestational age, postconceptional age and birth weightneeds to be taken into account when deciding if a blood pressure is normal in a neonate.

Hypertension occurs quite commonly in children and adolescents (2-9% depending on age, sex and ethnicity) and is associated with long term risks of ill-health. It is now recommended that children over the age of 3 have their blood pressure checked whenever they attend for routine medical care or checks, but high blood pressure must be confirmed on repeated visits before characterizing a child as having hypertension Blood pressure rises with age in childhood and, in children, hypertension is defined as an average systolic or diastolic blood pressure on three or more occasions equal or higher than the 95th percentile appropriate for the sex, age and height of the child. Prehypertension in children is defined as average systolic or diastolic blood pressure that is greater than or equal to the 90th percentile, but less than the 95th percentile. In adolescents, it has been proposed that hypertension and pre-hypertension are diagnosed and classified using the same criteria as in adults.

1.1.5.5. Prevention

Much of the disease burden of high blood pressure is experienced by people who are not labelled as hypertensive. Consequently, population strategies are required to reduce the consequences of high blood pressure and reduce the need for antihypertensive drug therapy. Lifestyle changes are recommended to lower blood pressure, before starting drug therapy. The 2004 British Hypertension Society guidelines proposed the following lifestyle changes consistent with those outlined by the US National High BP Education Program in 2002 for the primary prevention of hypertension:

maintain normal body weight for adults (e.g. body mass index 20–25 kg/m2)

reduce dietary sodium intake to <100 mmol/ day (<6 g of sodium chloride or <2.4 g of sodium per day)

engage in regular aerobic physical activity such as brisk walking (≥30 min per day, most days of the week)

limit alcohol consumption to no more than 3 units/day in men and no more than 2 units/day in women

consume a diet rich in fruit and vegetables (e.g. at least five portions per day);

Effective lifestyle modification may lower blood pressure as much an individual antihypertensive drug. Combinations of two or more lifestyle modifications can achieve even better results.

1.1.5.6. Management

Lifestyle modifications

The first line of treatment for hypertension is identical to the recommended preventative lifestyle changes and includes: dietary changes physical exercise, and weight loss. These have all been shown to significantly reduce blood pressure in people with hypertension. If hypertension is high enough to justify immediate use of medications, lifestyle changes are still recommended in conjunction with medication.

Dietary change such as a low sodium diet is beneficial. A long term (more than 4 weeks) low sodium diet in Caucasians is effective in reducing blood pressure, both in people with hypertension and in people with normal blood pressure. Also, the DASH diet, a diet rich in nuts, whole grains, fish, poultry, fruits and vegetables lowers blood pressure. A major feature of the plan is limiting intake of sodium, although the diet is also rich in potassium, magnesium, calcium, as well as protein. Different programs aimed to reduce psychological stress such a biofeedback, relaxation or meditation are advertised to reduce hypertension. However, overall efficacy is not greater than health education, with evidence being generally of low quality.

Medications

Several classes of medications, collectively referred to as antihypertensive drugs, are currently available for treating hypertension. Prescription should take into account the person's cardiovascular risk (including risk of myocardial infarction and stroke) as well as blood pressure readings, in order to gain a more accurate picture of the person's cardiovascular profile. Evidence in those with mild hypertension (SBP less than 160 mmHg and /or DBP less than 100 mmHg) and no other health problems does not support a reduction in the risk of death or rate of health complications from medication treatment.

If drug treatment is initiated the Joint National Committee on High Blood Pressure (JNC-7) recommends that the physician not only monitor for response to treatment but should also assess for any adverse reactions resulting from the medication. Reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. The aim of treatment should be to reduce blood pressure to <140/90 mmHg for most individuals, and lower for those with diabetes or kidney disease (some medical professionals recommend keeping levels below 120/80 mmHg). If the blood pressure goal is not met, a change in treatment should be made as therapeutic inertia is a clear impediment to blood pressure control.

Guidelines on the choice of agents and how best to step up treatment for various subgroups have changed over time and differ between countries. The best first line agent is disputed. The Cochrane collaboration, World Health Organization and the United States guidelines supports low dose thiazide-based diuretic as first line treatment. The UK guidelines emphasise calcium channel blockers (CCB) in preference for people over the age of 55 years or if of African or Caribbean family origin, with angiotensin converting enzyme inhibitors (ACE-I) used first line for younger people. In Japan starting with any one of six classes of medications including: CCB, ACEI/ARB, thiazide diuretics, beta-blockers, and alpha-blockers is deemed reasonable while in Canada all of these but alpha-blockers are recommended as options.

Drug combinations

The majority of people require more than one drug to control their hypertension. JNC7 and ESH-ESC guidelines advocate starting treatment with two drugs when blood pressure is >20 mmHg above systolic or >10 mmHg above diastolic targets. Preferred combinations are renin–angiotensin system inhibitors and calcium channel blockers, or renin–angiotensin system inhibitors and diuretics. Acceptable combinations include calcium channel blockers and diuretics, beta-blockers and diuretics, dihydropyridine calcium channel blockers and beta-blockers, or dihydropyridine calcium channel blockers with either verapamil or diltiazem. Unacceptable combinations are non-dihydropyridine calcium blockers (such as verapamil or diltiazem) and beta-blockers, dual renin–angiotensin system blockade (e.g. angiotensin converting enzyme inhibitor + angiotensin receptor blocker), renin–angiotensin system blockers and beta-blockers, beta-blockers and centrally acting agents. Combinations of an ACE-inhibitor or angiotensin II–receptor antagonist, a diuretic and an NSAID (including selective COX-2 inhibitors and non-prescribed drugs such as ibuprofen) should be avoided whenever possible due to a high documented risk of acute renal failure. The combination is known colloquially as a "triple whammy" in the Australian health industry. Tablets containing fixed combinations of two classes of drugs are available and while convenient for the people, may be best reserved for those who have been established on the individual components.

In the elderly

Treating moderate to severe hypertension decreases death rates and cardiovascular morbidity and mortality in people aged 60 and older. There are limited studies of people over 80 years old but a recent review concluded that antihypertensive treatment reduced cardiovascular deaths and disease, but did not significantly reduce total death rates. The recommended BP goal is advised as <140/90 mm Hg with thiazide diuretics being the first line medication in America, and in the revised UK guidelines calcium-channel blockers are advocated as first line with targets of clinic readings <150/90, or <145/85 on ambulatory or home blood pressure monitoring.

1.1.5.7. Resistant hypertension

Resistant hypertension is defined as hypertension that remains above goal blood pressure in spite of concurrent use of three antihypertensive agents belonging to different antihypertensive drug classes. Guidelines for treating resistant hypertension have been published in the UK and US.

1.1.6. Introduction to drug profile25-26

Name of Drug:- Losartan Potassium

Generic name:- Cozaar

Chemical name:- 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-

ylphenyl)benzyl]imidazole-5-methanol

monopotassium salt

Molecular Formula:- C22H22ClKN6O

Category:- Angiotensin ll receptor antagonist

Molecular structure:-

Molecular weight:- 461.01

Melting point:- 183.5-184.5 ºC

Dose:- Tablet:- 25mg,50mg and 100 mg

Therapeutic Category:- Anti-hypertensive

Solubility:- Freely soluble in water, soluble in alcohol, organic

Solvent like acetonitrile

PKa:- 4.9

Half-life(t1/2):- 1.5-2 hrs.

Volume of distribution(Vd):- 0.30 liter/kg or 34 kg/liter

Cmax:- 296±217ng/ml and 249±74ng/ml.

Therapeutic Range:- 12.5mg to 100mg

Tmax (hrs):- 1 hrs.

% Bioavaibility:- 33%

Losartan potassium is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

Losartan potassium is available as tablets for oral administration containing either 25 mg, 50 mg or 100 mg of losartan potassium and the following inactive ingredients: microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide.

Losartan potassium 25 mg, 50 mg and 100 mg tablets contain potassium in the following amounts: 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively. Losartan potassium 25 mg, Losartan potassium 50 mg, and Losartan potassium 100 mg may also contain carnauba wax.

Clinical pharmacology

Mechanism of Action

Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitiveinhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.

Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Pharmacokinetics

General

Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of 14C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.

The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours.

Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased). Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively.

Special Populations

Pediatric: Pharmacokinetic parameters after multiple doses of losartan (average dose 0.7 mg/kg, range 0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 1 below. Pharmacokinetics of losartan and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults. The principal pharmacokinetic parameters in adults and children are shown in the table below.

Geriatric and Gender: Losartan pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females.

Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about 2-times higher.

Drug Interactions

Losartan, administered for 12 days, did not affect the pharmacokinetics or pharmacodynamics of a single dose of warfarin. Losartan did not affect the pharmacokinetics of oral or intravenous digoxin. There is no pharmacokinetic interaction between losartan and hydrochlorothiazide. Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite. Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite. A somewhat greater interaction (approximately 40% reduction in the AUC of active metabolite and approximately 30% reduction in the AUC of losartan) has been reported with rifampin. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, another inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

1.1.7. Introduction to Excipients27-37

1.1.7.1. Hydroxy propylmethylcellulose27-29

a) Nonproprietary Names

BP: Hypromellose

JP: Hydroxy propylmethylcellulose

PhEur: Hypromellosum

USP: Hypromellose

b) Synonyms

Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC; Methocel;

Tylopur; Methylcellulose propylene glycol ether, methyl hydroxy propyl cellulose, Metolose.

c) Chemical Name and CAS Registry Number

Cellulose hydroxypropyl methyl ether [9004-65-3]

d) Empirical Formula and Molecular Weight

The PhEur 2005 describes hypromellose as a partly O-methylated and O-(2- hydroxypropylated) cellulose. It is available in several grades that vary in viscosity and extent of substitution. Grades may be distinguished by appending a number indicative of the apparent viscosity, in mPa s, of a 2 % w/w aqueous solution at 20°C.

e) Functional Category

Coating agent; film-former; rate-controlling polymer for sustained release;

stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent

f) Structural Formula:- Structure of HPMC

g) Applications in Pharmaceutical Formulation or Technology

Hypromellose is widely used in oral, ophthalmic and topical pharmaceutical formulations. In oral products, hypromellose is primarily used as a tablet binder, in film-coating, and as a matrix for use in extended-release tablet formulations. Concentrations between 2 % and 5 % w/w may be used as a binder in either wet- or dry-granulation processes. High-viscosity grades may be used to retard the release of drugs from a matrix at levels of 10–80 % w/w in tablets and capsules.

Depending upon the viscosity grade, concentrations of 2–20 % w/w are used forfilm- forming solutions to film-coat tablets. Lower-viscosity grades are used in aqueous film-coating solutions, while higher-viscosity grades are used with organic solvents. Examples of film coating materials that are commercially available include AnyCoat C, Spectracel, and Pharmacoat. Hypromellose is also used as a suspending and thickening agent in topical formulations. Compared with methylcellulose, hypromellose produces aqueous solutions of greater clarity, with fewer undispersed fibers present, and is therefore preferred in formulations for ophthalmic use. Hypromellose at concentrations between 0.45–1.0 % w/w may be added as a thickening agent to vehicles for eye drops and artificial tear solutions. Hypromellose is also used as an emulsifier, suspending agent, and stabilizing agent in topical gels and ointments. As a protective colloid, it can prevent droplets and particles from coalescing or agglomerating, thus inhibiting the formation of sediments. In addition, hypromellose is used in the manufacture of capsules, as an adhesive in plastic bandages, and as a wetting agent for hard contact lenses. It is also widely used in cosmetics and food products.

h) Description

Hypromellose is an odorless and tasteless, white or creamy-white fibrous or granular powder.

i) Solubility

Soluble in cold water, forming a viscous colloidal solution; practically insoluble in chloroform, ethanol (95 %), and ether, but soluble in mixtures of ethanol and dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and alcohol. Certain grades of hypromellose are soluble in aqueous acetone solutions, mixtures of dichloromethane and propan-2-ol, and other organic solvents.

j) Viscosity (dynamic)

A wide range of viscosity types are commercially available. Aqueous solutions are most commonly prepared, although hypromellose may also be dissolved in aqueous alcohols such as ethanol and propan-2-ol provided the alcohol content is less than 50 % w/w. Dichloromethane and ethanol mixtures may also be used to prepare viscous hypromellose solutions. Solutions prepared using organic solvents tend to be more viscous; increasing concentration also produces more viscous solutions.

Table 1.5:- Typical viscosity values for 2 % w/v aqueous solutions of Methocel. Viscosities measured at 20 °C.

Methocel product

Nominal viscosity

(mPa s)

Methocel K100 Premium LVEP

100

Methocel K4M Premium

4000

Methocel K15M Premium

15000

Methocel K100M Premium

100 000

Methocel E4M Premium

4000

Methocel F50 Premium

50

Methocel E10M Premium CR

10 000

Methocel E3 Premium LV

3

Methocel E5 Premium LV

5

Methocel E6 Premium LV

6

Methocel E15 Premium LV

15

Methocel E50Premium LV

50

1.1.7.2. Microcrystalline cellulose30-31

a) Nonproprietary Names

BP: Microcrystalline cellulose

JP: Microcrystalline cellulose

PhEur: Cellulosum microcristallinum

b) Synonyms

Avicel PH; Celex; cellulose gel; Celphere; Ceolus KG; crystalline cellulose; E460; Emcocel; Ethispheres; Fibrocel; Pharmacel;Tabulose; Vivapur.

c) Chemical Name and CAS Registry Number

Cellulose [9004-34-6]

d) Empirical Formula and Molecular Weight

(C6H10O5)n Ì´36 000 Where n Ì´ 220.

e) Functional Category

Adsorbent; suspending agent; tablet and capsule diluent; tablet disintegrant

f) Applications in Pharmaceutical Formulation or Technology

Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a binder/diluent in oral tablet and capsule formulations where it is used in both wetgranulation and direct-compression processes. In addition to its use as a binder/diluent, microcrystalline cellulose also has some lubricant and disintegrant properties that make it useful in tableting. Microcrystalline cellulose is also used in cosmetics and food products.

g) Description

Microcrystalline cellulose is purified, partially depolymerized cellulose that occurs as a white, odorless, tasteless, crystalline powder composed of porous particles. It is commercially available in different particle sizes and moisture grades that have different properties and applications.

Uses of microcrystalline cellulose.

Use Concentration (%)

Adsorbent 20-90

Antiadherent 5-20

Capsule binder/diluents 20-90

disintegrants 5-15

binder/diluents 20-90

1.1.7.3. Polyvinylpyrrolidone32-34

a) Synonyms

Polyvidone, povidone, PVP

b) Fuctional category

Disintegrant, dissolution aid, suspending agent, tablet binder.

c) Applications in Pharmaceutical Formulation or Technology

Although povidone is used in a variety of pharmaceutical formulations, it is primarily used in solid-dosage forms. In tableting, povidone solutions are used as binders in wet granulation processes. Povidone is also added to powder blends in the dry form and granulated in situ by the addition of water, alcohol, or hydroalcoholic solutions. Povidone is used as a solubilizer in oral and parenteral formulations and has been shown to enhance dissolution of poorly soluble drugs from solid-dosage forms. Povidone solutions may also be used as coating agents.

d) Description

Povidone occurs as a fine, white to creamy-white colored, odorless or almost odorless, hygroscopic powder. Povidone with K-values equal to or lower than 30 are manufactured by spray-drying and occur as spheres. Povidone K-90 and higher K value povidones are manufactured by drum drying and occur as plates.

e) Solubility

Freely soluble in acids, chloroform, ethanol (95 %), ketones, methanol, and water, practically insoluble in ether, hydrocarbons, and mineral oil. In water, the concentration of a solution is limited only by the viscosity of the resulting solution, which is a function of the K-value.

1.1.7.4. Magnesium Stearate35

Non proprietary Names

BP: Magnesium stearate

JP: Magnesium stearate

PhEur: Magnesii stearas

USPNF: Magnesium stearate

Synonyms

Magnesium octadecanoate; octadecanoic acid, magnesium salt; stearic acid, magnesium salt

Chemical Name and CAS Registry Number

Octa decanoic acid magnesium salt [557-04-0]

Structural Formula

[CH3 (CH2)16COO] 2Mg

Functional Category

Tablet and capsule lubricant

Applications in Pharmaceutical Formulation or Technology

Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25 % and 5.0 % w/w. It is also used in barrier creams.

Description

Magnesium stearate is fine white, light white, precipitated or miled, impalpable or low bulk density powder, having a faint order of stearic acid and a characteristic taste. The powder is greasy to touch and readily adhere to the skin.

1.1.7.5. Aerosil35

Nonproprietary Names

BP: Colloidal anhydrous silica PhEur: Silica colloidalis anhydrica USPNF: Colloidal silicon dioxide

Synonyms

Aerosil; Cab-O-Sil; Cab-O-Sil M-5P; colloidal silica; fumed silica; light anhydrous silicic acid; silicic anhydride; silicon dioxide fumed; Wacker HDK.

Chemical Name and CAS Registry Numbe