The Cause Primary Hypertension

Published Date: 02 Nov 2017

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 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 Number

Silica [7631-86-9]

Empirical Formula and Molecular Weight

SiO2 ; M.wt:60.08

Structural Formula

SiO2

Functional Category

Adsorbent; anticaking agent; emulsion stabilizer; glidant; suspending agent; tablet disintegrant; thermal stabilizer; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Colloidal silicon dioxide is widely used in pharmaceuticals, cosmetics, and food products. Its small particle size and large specific surface area give it desirable flow characteristics that are exploited to improve the flow properties of dry powders in a number of processes such as tableting. Colloidal silicon dioxide is also used to stabilize emulsions and as a thixotropic thickening and suspending agent in gels and semisolid preparations. With other ingredients of similar refractive index, transparent gels may be formed. The degree of viscosity increase depends on the polarity of the liquid (polar liquids generally require a greater concentration of colloidal silicon dioxide than nonpolar liquids). Viscosity is largely independent of temperature.

Table 1.6:- Uses of colloidal silicon dioxide.

Use

Concentration (%)

Aerosols

0.5-2.0

Emulsion stabilizer

1.0-5.0

Glidant

0.1-0.5

Suspending and thickening agent

2.0-10.0

Description

Colloidal silicon dioxide is a submicroscopic fumed silica with a particle size of about 15 nm. It is a light, loose, bluish-white colored, odorless, tasteless, nongritty amorphous powder.

1.1.7.6. Polyehtylene oxide (Polyox WSR 303)36-37

Polyethylene oxide (PEO) polymers available commercially under the trade name of POLYOXâ„¢, water soluble resins (WSR), are novel materials with unique properties. They have found a number of uses in pharmaceutical applications. PEO can be used in extended release (ER) matrices osmotic pumps, in mucosal bio-adhesives, in melt extrusion and in gastro-retentive dosage forms.

Polyethylene oxide (PEO) polymers, available commercially under the trade name of POLYOXâ„¢ water soluble resins (WSR), are novel materials with unique properties. They have found a number of uses in pharmaceutical applications such as extended release (ER) matrices, osmotic pumps, mucosal bioadhesives, hot melt extrusion and gastro-retentive dosage forms. PEO polymers are nonionic, highly swelling, thermoplastic and soluble in water, and selected organic solvents.

POLYOX™ polymers are free flowing white crystalline powders with an average particle size of around 150 μm. They are nonionic, highly swelling, thermoplastic and soluble in water and selected organic solvents.

The purpose of this work was to characterize the physical and mechanical properties of POLYOXâ„¢ in relation to the tablet manufacturing processes, for extended release (ER) matrix applications.

Particle Appearance

Appearance of powder particles was assessed with the aid of a stereomicroscope (S8 APO, Leica Microsystems Ltd, UK). Photomicrographs of the samples were taken using a digital camera (DFC420, Leica Microsystems Ltd, UK) at x40 magnification.

Powder Flow

Flow properties of POLYOX™ powders were determined by calculating the Carr’s index as shown below, Equation 1. A tap density tester (Sotax, UK) was used to measure the bulk volume (V0) and the final tapped volume (Vf) of a 100 g sample for all tested materials. The Carr’s index, or the % compressibility of a powder due to tapping, can give some indication of material flow properties.

Compressibility Index = (V0 - Vf) x 100

V0

In addition, powder flow was assessed during rotary tablet manufacture (see below) by measuring weight variation of the produced compacts.

Table 1.7:- Various Viscosity Grade of Polyox

POLYOX NF Grade

Approx. Molecular

Weight

Viscosity at 25ºC (cP)

WSR N-80 NF

200,000

55 – 90 (5% solution)

WSR N-750 NF

300,000

600 - 1,200 (5% solution)

WSR-301 NF

4,000,000

1,650 - 5,500 (1% solution)

WSR Coagulant NF

5,000,000

5,500 - 7,500 (1% solution)

WSR-303 NF

7,000,000

7,500 - 10,000 (1% solution)

Moisture Content

Moisture content of the POLYOX™ samples was determined by using a loss on drying (LOD) method in an oven (Heraeus, UK) at 105ºC. The test was conducted on 1 g samples. The samples were re-weighed after drying in the oven for 60 minutes.