Pharma Tips

Direct Compression Tablet

By: Pharma Tips | Views: 11587 | Date: 29-Jun-2010

Over the past hundred years tablet manufacturers have developed materials and processes that can produce compressed tablets containing a precise amount of an active pharmaceutical ingredient (API) at high speed and at relatively low cost.

Direct Compression Tablet

1.1 Introduction to Direct Compression
Over the past hundred years tablet manufacturers have developed materials and processes that can produce compressed tablets containing a precise amount of an active pharmaceutical ingredient (API) at high speed and at relatively low cost. The development in the field of APIs, excipients and tableting machines during the past decades has made tablet manufacturing a science and the tablets the most commonly used dosage form ,  The ease of manufacturing, convenience in administration, accurate dosing, and stability compared to oral liquids, tamperproofness compared to capsules, safe compared to parental dosage forms makes it a popular and versatile dosage form. Experts in the art of tableting are aware with the basic art of tableting by the three well-known methods, i.e. wet granulation, roller compaction and direct compression1,2,3. The pros and cons of wet granulation and roller compaction are well documented in the literature , ,  Prior to the late 1950s, the literature contained few references on the direct compression of pharmaceuticals. A great deal of attention has been given to both product and process development in the recent years. The availability of new materials, new forms of old materials and the invention of new machinery has allowed the production of tablets by simplified and reliable methods1 .  In early 1960’s, the introduction of spray dried lactose (1960) and Avicel (1964) had changed the tablet manufacturing process and opened avenues of direct compression tableting.  Shangraw 4 conducted a survey of 58 products in United States of America for the preference for the granulation process. The results were in favour of direct compression. Of the five processes listed in the survey, the average score (1.0 being the perfect score) for direct compression was 1.5 compared to wet massing and fluid bed drying (2.0), wet massing and tray drying (2.5), all-in-one (3.3) and roller compaction (3.6). About 41% of the companies indicated that direct compression was the method of choice, and 41.1% indicated that they used both direct compression and wet granulation. Only 1.7% of the respondents indicated that they never used direct compression and 15.5% indicated that the process was not recommended. Previously, the word “direct compression” was used to identify the compression of a single crystalline compound (i.e. sodium chloride, potassium chloride, potassium bromide, etc.) into a compact form without the addition of other substances. Current usage of the term “direct compression” is used to define the process by which tablets are compressed directly from the powder blends of active ingredients and suitable excipients. No pre-treatment of the powder blends by wet or dry granulation is involved (5). The simplicity of the direct compression process is apparent from a comparison of the steps involved in the manufacture of tablets by wet granulation, roller compaction and direct compression techniques (4) (See Table 1). It has been estimated that less than 20 percent of pharmaceutical materials can be compressed directly into tablets (4). The rest of the materials lack flow, cohesion or lubricating properties necessary for the production of tablets by direct compression. The use of directly compressible adjuvants may yield satisfactory tablets for such materials.

Table 1: Comparison of major steps involved in the granulation methods.
StepDirect CompressionDry GranulationWet Granulation
1Mixing/blending of API & Adjuvants 
Mixing/blending of API & Adjuvants
Mixing/blending of API & Adjuvants
2CompressionCompression in to slug
Preparation of binder solution
3Size reduction of slug & sieving
Massing of binder solution of step 2 with powder mixture of step 1
4Mixing of granules with pharmaceutical aid/s
Wet screening of step 1
5CompressionDrying of wet granulation
6Resifting of dry granules & blending with the pharmaceutical aid/s

1.1.1 Introduction to Directly Copressible Adjuvants
The International Pharmaceutical Excipients Council (IPEC) defines excipient as “Substances, other than the API in finished dosage form, which have been appropriately evaluated for safety and are included in a drug delivery system to either aid the processing or to aid manufacture, protect, support, enhance stability, bioavailability or patient acceptability, assist in product identification, or enhance any other attributes of the overall safety and effectiveness of the drug delivery system during storage or use”5. Solvents used for the production of a dosage form but not contained in the final product are considered to be excipients, i.e. the granulation fluids, which might be dried off later, should comply with relevant requirements of pharmacopoeia unless adequately justified. Excipients no longer maintain the initial concept of “inactive support” because of the influence they have both over biopharmaceutical aspects and technological factors. The desired activity, the excipients equivalent of the active ingredient’s efficacy, is called its Functionality. The inherent property of an excipient is its functionality in the dosage form. Determination of an excipient’s functionality is important to the excipient manufacturer in its assessment of the proper level of GMP, and yet the drug manufacturer may withhold this information until well into the development process.
 In order to deliver a stable, uniform and effective drug product, it is essential to know the properties of the active ingredient alone and in combination with all other ingredients based on the requirements of the dosage form and processes applied. Excipients are usually produced by batch process; hence, there is a possibility of batch-to-batch variation from the same manufacturer. Excipients obtained from the different sources may not have identical properties with respect to use in a specific formulation. To assure interchangeability in such circumstances, users may wish to ascertain equivalency in final performance or determine such characteristics before use. Such tests are thus related to the functionality, that the excipient impart to a specific formulation.
 In order to manufacture any finished product with consistent quality, standardization of raw materials in the drug formulation is necessary for its acceptance by regulatory authorities and pharmaceutical formulators. Unfortunately, such performance standards have not been included in pharmacopoeia primarily because their specifications have always been based on chemical purity and because it is not possible to standardize Performance criteria. Pharmacopoeial standards do not take into account particle characteristics or powder properties, which determine functionality of excipients. Control of functionality is important as a control of identity and purity. The following reasons can be cited:
1.Many excipients have multiple functions (e.g. microcrystalline cellulose, starch).
2.There is lack of awareness that the excipients behave differently, depending upon the vendor (i.e. microcrystalline cellulose).
As a consequence, excipients with optimal functionality are needed to ensure smooth tablet production on modern machines. The introduction of special force feeder to improve flow of granules from hopper marked a significant advancement in direct compression technology

1.1.2 Ideal Requirements of Directly Compressible Adjuvants
1. Flowability
The directly compressible adjuvant should be free flowing. Flowability is required in case of high-speed rotary tablet machines, in order to ensure homogenous and rapid flow of powder for uniform die filling. During the short dwell-time (milliseconds), the required amount of powder blend should be transferred into the die cavities with reproducibility of + 5%. Many common manufacturing problems are attributed to incorrect powder flow, including non-uniformity in blending, under or over dosage and inaccurate filling.

2. Compressibiliy
Compressibility is required for satisfactory tableting, i.e., the mass must remain in the compact form once the compression force is removed. Few excipients can be compressed directly without elastic recovery. Hence, the directly compressible diluent should have good compressibility, i.e. relation between compaction pressure and volume. 

3. Dilution Potential
Dilution potential can be defined as the amount of an active ingredient that can be satisfactorily compressed in to tablets with the given directly compressible excipient. A directly compressible adjuvant should have high dilution potential so that the final dosage form has a minimum possible weight. The dilution potential is influenced by the compressibility of the active pharmaceutical ingredient. 

4. Re-workability
A directly compressible adjuvant should be capable of being reworked without loss of flow or compressibility. On recompression, the adjuvant should exhibit satisfactory tableting characteristics. 

5. Stability
It is the ability of adjuvant to remain unchanged chemically and physically. The directly compressible adjuvant should not exhibit any physical or chemical change on ageing and should be stable to air, moisture and heat.

6. Control Particle Size
A directly compressible adjuvant should have a particle size equivalent to the active ingredients present in the formulation. The particle size distribution should be consistent from batch to batch. Reproducible particle size distribution is necessary to achieve uniform blending with the active ingredient(s) in order to avoid segregation. 

7. Inertness
Filler-binders should not accelerate the chemical and/or physical degradation of the API(s) or excipients. It should not interfere with the biological availability of active ingredient/s. It should be compatible with all the adjuvants present in the formulation. It should be physiologically inert5. It should not interfere with the disintegration or dissolution of the active ingredient. It should be colourless and tasteless. It should be relatively cost effective and available in desired time. It should accept colorants uniformly. It should show low lubricant sensitivity. It should show batch-to-batch reproducibility of physical and physicomechanical properties. It should possess proper mouth fill, which is defined as the feel or the sensation in the mouth, produced when the excipient is used in chewable tablets
Table 2: Ideal requirements, advantages and limitations of direct compression
FlowabilityCost effective productionSegregation
CompressibilityBetter solubility of APIVariation on functionality
Dilution potentialFaster dissolutionLow dissolution potential
ReworkabilityLess wear & tear punchesReworkability
StabilitySimplified validationPoor compressibility of API
Controlled particle sizeLower microbial contaminationLubrication sensitivity

1.1.3 Advantages of Direct Compression
1. Cost Effectiveness
The prime advantage of direct compression over wet granulation is economic since the direct compression requires fewer unit operations. This means less equipment, lower power consumption, less space, less time and less labor leading to reduced production cost of tablets. 

2. Stability
Direct compression is more suitable for moisture and heat sensitive APIs, since it eliminates wetting and drying steps and increases the stability of active ingredients by reducing detrimental effects. Changes indissolution profiles are less likely to occur in tablets made by direct compression on storage than in those made from granulations. This is extremely important because the official compendium now requires dissolution specifications in most solid dosage forms. 

3. Faster Dissolution
Disintegration or dissolution is the rate limiting step in absorption in the case of tablets of poorly soluble API prepared by wet granulation. The tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster dissolution. 

4. Less wear & tear of punches
The high compaction pressure involved in the production of tablets by slugging or roller compaction can be avoided by adopting direct compression. The chances of wear and tear of punches and dies are less. 

5. Simplified Validation
Materials are "in process" for a shorter period of time, resulting in less chance for contamination or cross contamination, and making it easier to meet the requirement of current good manufacturing practices. Due to fewer unit operations, the validation and documentation requirements are reduced. Due to the absence of water in granulation, chance of microbial growth is minimal in tablets prepared by direct compression.

1.1.4 Limitations of Direct Compression
1. Segregation
Direct compression is more prone to segregation due to the difference in density of the API and excipients. The dry state of the material during mixing may induce static charge and lead to segregation. This may lead to the problems like weight variation and content uniformity. 

2. Cost
Directly compressible excipients are the speciality products produced by patented spray drying, fluid bed drying, roller drying or co-crystallization. Hence, the products are relatively costly than the respective raw materials. 

3. Low dilution potential
Most of the directly compressible materials can accommodate only 30-40 % of the poorly compressible active ingredients like acetaminophen that means the weight of the final tablet to deliver the 500 mg of acetaminophen would be more than 1300 mg. The large tablets may create difficulty in swallowing. 

4. Re-workability
All the spray-dried directly compressible adjuvants show poor reworkability since on preparation of tablets the original spherical nature of the excipient particles is lost. API that has poor flow properties and/or low bulk density is difficult to process by direct compression. 

5. Lubricant sensitivity
Lubricants have a more adverse effect on the filler, which exhibit almost no fracture or shear on compression (e.g. starch 1500). The softening effects as well as the hydrophobic effect of alkaline stearates can be controlled by optimising the length of blending time to as little as 2-5 min.

6. Variation in functionality
There is a lack of awareness in some situations that the excipient behave differently, depending upon the vendor so much so that substitution from one source to that of another is not possible. Hence, there is a need for greater quality control in purchasing of raw material to assure batch uniformity.

1.1.5 Methods of Preparing Directly Compressible Excipients
Directly compressible adjuvant can be prepared by various methods. The outline and main features of the methods are depicted in Table 3. Co-processing is the one of the most widely explored and commercially utilized method for the preparation of directly compressible adjuvants. Hence, co-processing is discussed in more depth in the present review.

Table  3:  Summary of various methods used to prepare directly compressible adjuvants
ChemicalmodificationRelative expensive,
Time consuming,
Require toxicological dataEthyl cellulose, Methyl cellulose,
Hydroxy propyl methyl cellulose,
Na-CMC, Cyclodextrin.
Physical modifictionRelatively simple & economicalDextrates or compressible sugurs, sorbitol.
Grinding &/or SievingCompressibility may alter because of Change in partical properties such as Surface area.α-lactosemonohydrate(100#), Dibasiccalciumphosphate.

CrystlizationIpart flowability to excipients but not necessarily self-binding properties. β-lactose, Dipac.
Spray Dryingspherical shape & uniform size gives spray dried matirials, good fowability & poor workability. Spray dried lactose, Emdex, fast flow lactose, Avicle PH, Karion instant, TRI-CAFOS S, Advantose 100. 
GranulationTransformation of small,cohesive & poorly flowable powders. Granulated lacitol Tabletose.
DehydrationIncreased binding properties by thermal & chemical dehydration.Anhyrous α-lactose

1.1.6 Co-Processing
Co-processing is another way that new excipients are coming to market without undergoing the rigorous safety testing of a completely new chemical. It can be defined as combining two or more established excipients by an appropriate process. Co-processing of excipients could lead to the formation of excipients with superior properties compared to the simple physical mixtures of their components. The main aim of co-processing is to obtain a product with added value related to the ratio of its functionality/price. Development of co-processed directly compressible adjuvant starts with the selection of the excipients to be combined, their targeted proportion, selection of preparation method to get optimized product with desired physico-chemical parameters and it ends with minimizing avoidance with batch-to-batch variations. An excipient of reasonable price has to be combined with the optimal amount of a functional material in order to obtain integrated product, with superior functionality than the simple mixture of components. Co-processing is interesting because the products are physically modified in a special way without altering the chemical structure. A fixed and homogenous distribution for the components is achieved by embedding them within minigranules. Segregation is diminished by adhesion of the actives on the porous particles making process validation and in process control easy and reliable. The randomized embedding of the components in special minigranules minimizes their anisotropic behaviour. So, deformation can occur along any plane and multiple clean surfaces are formed during the compaction process. Thus, the use of the co-processed excipient combines the advantages of wet granulation with direct compression. The use of one-body components is justified if it results in a potentiation of the functionalities over that of the mere dry blend of the components prepared by gravity mixture. This synergistic effect should improve the quality of the tablet equally in all aspects ranging from hardness to dissolution and/or stability. Excipient mixtures in co-processing are produced to make use of the advantages of each component and to overcome specific disadvantages, if any. Most important characteristics are the binding and blending properties of the co-processed excipients, which must be better than those of a physical mixture of the starting materials. Cost is another factor to be considered in the selection of co-processed product. Major limitation of co-processed excipient mixture is that the ratio of the excipients in a mixture is fixed and in developing a new formulation, a fixed ratio of the excipients may not be an optimum choice for the API and the dose per tablet under development. Coprocessed adjuvant lacks the official acceptance in pharmacopoeia. For this reason, a combination fillerbinder will not be accepted by the pharmaceutical industry until it exhibits significant advantages in the tablet compaction when compared to the physical mixtures of the excipients. Although the spray-crystallized dextrose-maltose (Emdex) and compressible sugar are co-processed products, they are commonly considered as single components and are official in USP/NF. 

Table 4: Co-processed directly compressible excipients
Brand NameAdjuvantsManufacurer, Country
CellactoseMCC, LactoseMeggle, Germany.
XylitabXylitol, Na CMCMeggle, Germany.
LudipressLactose, PVP, CrosspovidoneBASF, Germany.
StarlacLactose, MaizestarchRoquette, France.
Pharmatose DLC 40Anhydrous lactose, lactitolDMV, Netherlands.
Avicel CE 15MCC, Guar GumFMC, USA.
CelocolMCC, Calcium phosphateFMC, USA.
ProsolvMCC, Coloidial SilicaPenwest.
Di-pacSucrose, DextrinAmerican sugur, USA.
Advantose FS 95Fructose, starchSPI polysol, France.
Advantose 100MaltoeSPI polysol, France.
Barcoft CS 90Cacium carbonate,StarchSPI polysol, France.
Barcoft premix St.Al-hydroxide,Mg-hydroxide, SorbitolSPI polysol, France.
Plasdone S-630Vinyl acetate, vinyl pyrrolidoneISP. USA.
Carbofarma G10Calcium CarbonateResins industries, Argentina.
Carbofarma G11MaltodextrinResins industries, Argentina.

1.2.1 Introduction to Ludipress.
Chemical  Name:  Lactose, povidone, crospovidone

CAS No:  5989-81-1 + 9003-39-8

Quality Standard: The formulated ingredients lactose monohydrate, Kollidon 30 and Kollidon CL correspond to the current monographs in Ph.Eur., USP/NF and JP.

Applications: The main application is for direct compression, but is also suitable as a filler for hard gelatin capsules.

1.2.2 Introduction to Ludipress LCE.
Chemical Name: Lactose and Povidone.

CAS NO: 5989-81-1+9003-39

Quality Standard: The formulated ingredients lactose monohydrate and Kollidon 30 correspond to the current monographs in Ph.Eur., USP/NF and J.P.

Applications: The main application is for direct compression for use in chewable                                                                                                                                                                                                                                                                                                                                                                                                                                                        tablets and lozenges, for effervescent tablets and as bulking agent for modified release formulations.
1.3.1 Introduction to Acetazolamide
1. Description
Brand Name: Acetameb tablet, Acetamine tablet, Diamox Tablet, etc.
Category: Diuretic, anti glaucoma, anti epilepsy
Empirical Formula:C4H6N4O3S2
Nomenclature: N-(5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl)-acetamide
Molecular Weight: 222.248gm/mol
Appearance: Lightish yellow to white crystalline powder
Solubility: Very slightly soluble in water, slightly soluble in alcohol
Storage: Store in a well closed container 
2.  Pharmacokinetics: 
Absorption: well absorbed orally
Onset of action: 2 hours; I.V.: 2 minutes 
Peak effect: Capsule, extended release: 8-12 hours; I.V.: 15 minutes; Tablet: 2-4 hours 
Duration: Inhibition of aqueous humor secretion: Capsule, extended release: 18-24 hours; I.V.: 4-5 hours; Tablet: 8-12 hours 
Distribution: Erythrocytes, kidneys; blood-brain barrier and placenta; distributes into milk (~30% of plasma concentrations) 
Excretion: Urine (70% to 100% as unchanged drug) 

3.  Pharmacological Actions:
Acetazolamide is carbonic anhydrase enzyme inhibitor, present in renal tubular cell of gastric mucosa, exocrine pancreas, cilliary body of eye, brain.Carbonic anhydrase is an enzyme which catalyse the reversible reaction H2O+CO2  to H2CO3,carbonic acid spontaneously ionizes into H+ and CO3- Thus H+ ion secretion take place and H+ exchanges with luminal Na+ through Na+-H+ antiporter. This distal Na+ exchange take place only with K+ which is lost in excess.
4. Uses: 
Acetazolamide is often used in the treatment of various diseases. 
For glaucoma sufferers, the drug decreases fluid formation in the eye resulting in lower intraocular pressure. 
In epilepsy, its main use is in absence seizures, with some benefit in other seizure syndromes. It is also used to decrease generation of cerebrospinal fluid in benign intracranial hypertension and has shown efficacy in autosomal dominant hyperkalemic periodic paralysis.
Acute mountain sickness:Acetazolamide is sometimes taken prophylactically, anywhere between 125 milligrams (mg) to 500 mg per day, starting a few days before going to the higher altitude. Such use is recommended for those ascending from sea level to 3000 meters (9800 feet) in one day, or for those ascending more than 600 meters (2000 feet) per day once above an altitude of 2500 meters (8200 feet).
The drug forces the kidneys to excrete bicarbonate, the conjugate base of carbonic acid. By increasing the amount of bicarbonate excreted in the urine, the blood becomes more acidic. Acidifying the blood stimulates ventilation, which is beneficial during acclimatizatio.
5. Adverse effects: 
Cardiovascular: Flushing 
Central nervous system: Ataxia, confusion, convulsions, depression, dizziness, drowsiness, excitement, fatigue, headache, malaise 
Dermatologic: Allergic skin reactions, photosensitivity, Stevens-Johnson syndrome, urticaria 
Endocrine & metabolic: Electrolyte imbalance, growth retardation (children), hyperglycemia, hypoglycemia, hypokalemia, hyponatremia, metabolic acidosis 
Gastrointestinal: Appetite decreased, diarrhea, nausea, taste alternation, vomiting 
Genitourinary: Crystalluria, glycosuria, hematuria, renal failure 
Hematological: Agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia, thrombocytopenic purpura 
Hepatic: Cholestatic jaundice, hepatic insufficiency, liver function tests abnormal 
Neuromuscular & skeletal: Flaccid paralysis, paresthesia 
Ocular: Myopia 
Otic: Hearing disturbance, tinnitus 
Miscellaneous: Anaphylaxis.
6. Dose and dose schedule: 
Note: I.M. administration is not recommended because of pain secondary to the alkaline pH.
Oral: 8-30 mg/kg/day or 300-900 mg/m 2 /day divided every 8 hours 
I.V.: 20-40 mg/kg/24 hours divided every 6 hours, not to exceed 1 g/day 
Edema: Oral, I.V.: 5 mg/kg or 150 mg/m 2 once every day 
Epilepsy: Oral: 8-30 mg/kg/day in 1-4 divided doses, not to exceed 1 g/day; sustained release capsule is not recommended for treatment of epilepsy 
Chronic simple (open-angle): Oral: 250 mg 1-4 times/day or 500 mg sustained release capsule twice daily 
Secondary, acute (closed-angle): I.V.: 250-500 mg, may repeat in 2-4 hours to a maximum of 1 g/day 
Edema: Oral, I.V.: 250-375 mg once daily 
Epilepsy: Oral: 8-30 mg/kg/day in 1-4 divided doses; sustained release capsule is not recommended for treatment of epilepsy 
Mountain sickness: Oral: 250 mg every 8-12 hours (or 500 mg extended release capsules every 12-24 hours) 
Therapy should begin 24-48 hours before and continue during ascent and for at least 48 hours after arrival at the high altitude 
Urine alkalinization (unlabeled use): Oral: 5 mg/kg/dose repeated 2-3 times over 24 hours 
Respiratory stimulant in COPD (unlabeled use): Oral, I.V.: 250 mg twice daily 
 Oral: Initial: 250 mg twice daily; use lowest effective dose
7. Contraindication:
Acetazolamide should not be taken by individuals if they have
sickle cell anemia 
allergic to sulfa medications 
allergic to any carbonic anhydrase inhibitor 
liver or kidney disease 
adrenal gland failure (i.e. Addison's disease) 
pregnant or nursing mothers 
8. Drug Interactions:
Inhibits CYP3A4 (weak) 
Amphetamines: Urinary excretion of amphetamine may be decreased; magnitude and duration of effects may be enhanced. 
Cyclosporine trough concentrations may be increased resulting in possible nephrotoxicity and neurotoxicity. 
Digitalis toxicity may occur if hypokalemia is untreated. 
Lithium: Acetazolamide increases lithium excretion; lithium serum levels may be decreased. 
Methenamine: Urinary antiseptic effect may be prevented by Acetazolamide. 
Phenytoin: Serum concentrations of Phenytoin may be increased; incidence of osteomalacia may be enhanced or increased in patients on chronic Phenytoin therapy. 
Primidone serum concentrations may be decreased. 
Quinidine: Urinary excretion of Quinidine may be decreased and effects may be enhanced. 
Salicylate use may result in carbonic anhydrase inhibitor accumulation and toxicity including CNS depression and metabolic acidosis 

1.3.2 Introduction to Metformin HCl
1. Description
 Brand Name: Glucophage, Glycomate etc.
Category: Anti Diabatic.
Empirical Formula:C4H11N5HCL
Molecular Weight: 165.63gm/mol
Appearance:  off -white crystalline compound.
Solubility: Freely soluble in water & practically soluble in alcohol and aceton.
Storage: Store in a well closed container. 
2.  Pharmacokinetics: 
Absorption: well absorbed orally
Onset of action: 3-4 hour.
Distribution: Erythrocyte mass may be compartment of distribution.
Elimination plasma half life: approx. 6.2hr.
Excretion: 90% drug excrited in urine with in 24hr.

3.  Uses:
Pediatric Use
The safety and effectiveness of GLUCOPHAGE for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of GLUCOPHAGE in this age group is supported by evidence from adequate and well-controlled studies of GLUCOPHAGE in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults
Geriatric Use
Controlled clinical studies of GLUCOPHAGE and GLUCOPHAGE XR did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, GLUCOPHAGE and GLUCOPHAGE XR should only be used in patients with normal renal function 
4.Adverse effects:
- Diarrhea
- Nausea & vomiting.
- Asthenia
- Fletuiense
- Injestion
5. Contraindication:
- Renal dysfunction
- Known hyper sensitive reactions.
-Metabolic acidosis.
6. Drug intractions:
Glyburide: In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain.
Furosemide: A single-dose, metformin-furosemide dr ug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration.Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

2.1 Review of Work Done On Co-Processed Excipients.
Gonnissen et al.,  (2007) developed a continuous production of directly compressible powders by coprocessing acetaminophen and carbohydrates via spray drying.  Binary and ternary powder mixtures containing drug substance and carbohydrates were prepared by co-spray drying and evaluated on spray drying processibility, powder hygroscopicity, flowability, and compactibility.  The influence of process parameters during spray drying on the compaction behaviour of drug/excipient mixtures was investigated via Heckel analysis.  Erythritol, lactose, maltodextrin, and mannitol were efficient in co-spray drying with acetaminophen.  However, lactose mixtures showed poor flowability.  Spray dried mixtures containing mannitol and erythritol were characterized as non-hygroscopic, highly dense, and good flowing powders. Mannitol increased tablet tensile strength in contrast with the poor compactibility of erythritol.  Manltodextrin was selected for further experiment because it provided excellent tablet tensile strength. The use of erythritol, maltodextrin and mannitol in binary drug/Excipient mixtures resulted in high process yields.  Compacts of erythritol, mannitol and maltodextrin were characterized by higher tablet tensile strength at higher spray drying temperature due to the increased particle fragmentation of erythritol and mannitol mixtures and increased plastic deformation of maltodextrin formulations.  A combination of erythritol, maltodextrin and mannitol was selected for further formulation and process optimization of co-spray dried powders for direct compression. 

John et al.,  (2006 ) evaluated a microcrystalline cellulose based excipient having improved compressibility, whether utilized in direct compression, dry granulation or wet granulation formulations, is disclosed. The excipient is an agglomerate of microcrystalline cellulose particles and an effective amount of surfactant, which, in preferred embodiments is an anionic surfactant present in amount ranging from about 0.1% to about 0.5%, by weight  of the microcrystalline cellulose, where in the microcrystalline cellulose and surfactant are in intimate association with each other. One preferred anionic surfactant utilized in the novel excipient is sodium lauryal sulphate.

Uhumwangho et al.,  (2004) investigated the effect of varying the compression pressure on the brittle fracture tendency of α- cellulose and lactose. Tablet tensile strength (T), Packing fraction(Pf), and brittle fracture index(BMI) were determined at different compression pressure (0.82, 1.22 and 1.63 M Pa). in another aspect of study,  α- cellulose and tapioca powders were mixed in various proportion to obtain powder of varying plastoelasticity.their tableting  characteristics T, Pf, & BFI wre also determined at the different compression pressure. The difference in the response of tablets to the change in compression pressure relates to the difference in the plastoelasticity of the material tested.

Tsuimin et al.,  (2000) modifed the physical properties of microcrystalline cellulose, the slurry form of this material was co-dried with cyclodextrin. MCC slurry was blended with at concentration of 10% - 50% w/w as a dried mass relative to MCC. The mixtures were than granulated with water and co-dried at 60oc for 12hr or until a constant weight was reached. Co-dried granules were pulverized, and the fraction between 61 and 150m in size was received. The powder and tableting properties of the co- dried product were compared to those of the various grades of the MCC and corresponding components and physical mixtures. The results showed that the products of MCC co-dried with significantly improved flowability was due to more rounded shape of the particles formed with this co-dried process. Moreover, the compactibility and  disintegration properties of the tablets produced from the co-dried products were even better than those using MCC alone, or various grade of MCC. In final conclusion , MCC c0-dried provides a useful Excipient for direct compression.

Olaf et al.,  (2003) compared tablet formulation of compound based lactose and starch (85:15% w/w) to pure substance and graded mixtures. Pressure- time-profiles, pressure-porosity-profiles and compactibility-plots help to evaluate tableting property. They studied in detail the disintegration and drug release from starlac compared to those of the physical mixture and this especially at higher maximum.

Rao et al.,  (1999) developed cheaper, indigenous, directly compressible lactose by spry drying slurry of lactose I.P. the modified lactose (spry dried lactose - SDL) was characterized by evaluating physicochemical property and flow behaviour and the results obtained were compared with those of marketed directly compressible lactose(MDL). The directly compressible  SDL & MDL was also evaluated by compression on a rotary tablet machine results indicated that SDL has the potential to be used as directly compressible lactose which replace imported direct compressible lactose. 

Gohel et al.,  (2003) developed co-processed adjuvant consisting of MCC, dibasic calcium phosphate di hydrate and croscarmellose sodium. The properties of each components were evaluated and tablets of Nimesulide  were prepared to evaluate  the functionalities of the co-processed diluents. It was determine that developed adjuvant exhibited satisfactory tablet charachteristics.

Jogani et al.,  (2005) formulated a novel multifunctional co-processed adjuvant consisting of three known diluents those shows different consolidation. The method of wet granulation was adopted for the preparation of co-processed mechanism. MCC and colloidal silicone dioxide, lactose monohydrate and dibasic calcium phosphate dehydrate were used as independent variable in a simple lattice design. Cross carmellose sodium was used 4% level intra granularly in all the batches the granules (44/120#) were for angle of repose, bulk density, tapped density  & carr’s index. The tablet of compressed adjuvants was characterized for crushing strength, friability and disintegration time. Multiple linear rgressions were adopted for evolved refined mathematical model. A check point method was prepared for evaluation of the particle size distribution, moisture uptake and dilution potential by using  nimesulide as model drug. The results shows that desiered product characters can be obtained by varying the quantity of MCC, lactose and DCP.           

Sengle et al.,  (2008) developed microsphere-based once-daily modified release tablet formulations of diltiazem hydrochloride (DH), a potent calcium channel blocker used in angina pectoris. For this purpose, DH-loaded microspheres were prepared by the solvent evaporation technique using Eudragit RS 100. The effect of variation in the drug/polymer ratio on the physical and release characteristics of the microspheres was investigated. After the selection of the suitable microspheres, tablets were compressed using Compritol 888 ATO, Ludipress and Cellactose 80 as different direct tableting agents and excipients. As a result, modified release tablet formulations of DH-loaded microspheres were designed successfully for oral administration once rather than two or three times a day in angina pectoris.

El-Maradny et al.,  (2007)  prepare cores containing the drug were prepared by direct compression using microcrystalline cellulose and Ludipress as hydrophilic excipients with the ratio of 1:1. Cores were then coated sequentially with an inner swelling layer of different swellable materials; either Explotab, Croscarmellose sodium, or Starch RX 1500, and an outer rupturable layer of different levels of ethylcellulose. The effect of the nature of the swelling layer and the level of the rupturable coating on the lag time and the water uptake were investigated. Drug release rate studies were performed using USP paddle method. Results showed the dependence of the lag time and water uptake prior to tablet rupture on the nature of the swelling layer and the coating levels. Explotab showed a significant decrease in the lag time, followed by Croscarmellose sodium and finally by Starch RX 1500. Increasing the level of ethylcellulose coating retarded the diffusion of the release medium to the swelling layer and the rupture of the coat, thus prolonging the lag time.

Hascicek et al.,  (2006) developed modified release tablet formulations containing diltiazem hydrochloride-loaded microspheres to be taken once rather than two or three times a day was attempted. For this purpose, ethylcellulose microspheres were prepared by emulsion-solvent evaporation technique. The influence of emulsifier type and drug/polymer ratio on production yield, encapsulation efficiency, particle size, surface morphology and in-vitro release characteristics of the microspheres was evaluated. Suitable microspheres were selected and tabletted using different tabletting agents, Ludipress, Cellactose80, Flow-Lac100 and excipients Compritol888 ATO, KollidonSR. Tablets were evaluated from the perspective of physical and in-vitro drug release characteristics. It was seen that type and ratio of the excipients played an important role in the tabletting of the microspheres. As a result, two tablet formulations containing 180 mg diltiazem hydrochloride and using either Compritol888 ATO or KollidonSR were designed successfully and maintained drug release for 24 h with zero order and Higuchi kinetics, respectively.

Cavallari C et al.,  (2005) prepared physical mixtures containing indomethacin and beta-lactose and alpha-lactose-based excipients (Ludipress and Cellactose). The mixtures were compacted with the aid of ultrasound, obtaining tablets, which were milled and sieved. Granules thus obtained were examined by optical microscopy and differential scanning calorimetry. The intense yellow color of the granules and the absence of indomethacin peak in thermograms suggest important modifications of indomethacin physical state; the drug thus modified appears to be spread on the excipient particle surface as a thin film, giving a lustrous appearance. No influence of ultrasound was observed on phase transition concerning lactose; only loss of water was important under high energy ultrasound. Dissolution profiles suggest an increased release of the drug from the systems treated with ultrasound at high energy, with respect to a traditional compaction; while no difference could be evidenced among the three excipients that, however, appear all suitable for this ultrasound-aided direct compression process.
Jogani et al.,  (2005) direct compression is the preferred method for the preparation of tablets. The present review outlines the importance of the functionality of the directly compressible adjuvants in the formulation of tablets. The co-processing is the most widely explored method for the preparation of directly compressible adjuvants because it is cost effective and can be prepared in-house based on the functionality required. Hence, the present review focuses on the properties of the co-processed directly compressible adjuvants available in the market.
Selim et al.,  (2005) prepared capsules of different formulations by using a hydrophilic polymer, xanthan gum and a filler Ludipress. Metformin hydrochloride, which is an anti-diabetic agent, was used as a model drug here with the aim to formulate sustained release capsules. In the first 6 formulations, metformin hydrochloride and xanthan gum were used in different ratio. Later, Ludipress was added to the formulations in a percentage of 8% to 41%. The total procedure was carried out by physical mixing of the ingredients and filling in capsule shells of size ?1?. As metformin hydrochloride is a highly water soluble drug, the dissolution test was done in 250 ml distilled water in a thermal shaker (Memmert) with a shaking speed of 50 rpm at 370C ± 0.50C for 6 hours. After the dissolution, the data were treated with different kinetic models. The results found from the graphs and data show that the formulations follow the Higuchian release pattern as they showed correlation coefficients greater than 0.99 and the sustaining effect of the formulations was very high when the xanthan gum was used in a very high ratio with the drug. It was also investigated that the Ludipress extended the sustaining effect of the formulation to some extent. But after a certain period, Ludipress did not show any significant effect as the pores made by the xanthan gum network were already blocked. It is found here that when the metformin hydrochloride and the xanthan gum ratio was 1:1, showed a high percentage of drug release, i.e. 91.80% of drug was released after 6 hours. But With a xanthan gum and metformin hydrochloride ratio of 6:1, a very slow release of the drug was obtained. Only 66.68% of the drug was released after 6 hours. The percent loading in this case was 14%. Again, when Ludipress was used in high ratio, it was found to retard the release rate more prominently.

Kapat et al.,  (2004) this work has focused on the effects of different hydroxypropylmethylcellulose (HPMC) types and HPMC :direct tabletting agent (DC-agent) ratio on Verapamil Hydrochloride (VRP HCl) release from monolayered and three-layered matrix tablets. Investigated polymers were Methocel K100LV, K15M, K100M and DC-agent was Ludipress® LCE. Eight formulations were prepared as monolayered matrix tablets while four formulations were prepared as three-layered matrix tablets by direct compression method. Drug release studies were carried out according to the method given for Delayed Release Articles in USP XXVII. HPMC types and ratios were found to be effective on drug release. Increasing amount and viscosity grade of HPMC resulted in a decrease in release of drug from the matrices. Tablets containing low viscosity grade HPMC at inner and outer layers presented release profiles close to or within the limits of pharmacopeia. Release data of three-layered matrix tablet (F12) and the reference product (Isoptin® -KKH) which were in agreement with USP XXVII criteria, were evaluated by mathematical models (zero order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas), difference factor (f1) and similarity factor.
Md. Selim Reza et al.,  (2003)  undertaken to investigate the effect of plastic, hydrophilic and hydrophobic types of polymers and their content level on the release profile of drug from matrix systems. As the physico-chemical nature of the active ingredients influence the drug retarding ability of these polymers, three different drugs were used to evaluate their comparative release characteristics in similar matrices. Matrix tablets of theophylline, diclofenac sodium and diltiazem HCl using Kollidon SR, Carnauba wax and Hydroxypropyl methylcellulose (HPMC-15cps) were prepared separately by direct compression process. The USP Basket method was selected to perform the dissolution test carried out in 250 ml 0.1N HCl for first two hours and 1000 ml phosphate buffer of pH 6.8 for ten hours.  Statistically significant differences were found among the drug release profile from different classes of polymeric matrices. The release kinetics was found to be governed by the type and content of polymer in the matrix system. Higher polymeric content (75%) in the matrix decreased the release rate of drug because of increased tortuosity and decreased porosity. At lower polymeric level (25%), the rate and extent of drug release was elevated. Carnauba wax was found to cause the strongest retardation of drug. On the otherhand, highest drug release was from HPMC matrices while Kollidon SR gave an intermediate release profile between these two polymers. Release rate was also found to be the function of physico-chemical nature of drug molecule. Theophylline and diltiazem HCl, being soluble in nature, released faster than diclofenac sodium from all matrix systems. The release mechanism was explored and explained with biexponential equation. Release profile showed a tendency to follow zero-order kinetics from HPMC matrix systems whereas Fickian (Case I) transport was predominant mechanism of drug release from Kollidon SR matrix system. The mean dissolution time (MDT) was calculated for all the formulations and the highest MDT value was obtained with Carnauba wax for all the drugs under investigate. The results generated in this study showed that the profile and kinetics of drug release were functions of polymer type, polymer level and physico-chemical nature of drug. A controlled plasma level profile of drug can be obtained by judicious combination of polymers and modulation of polymer content in the matrix system.

Budavári Z et al.,  (2001) clinical studies confirm that intake of folate, vitamin B6 and B12 above the current recommended dietary allowance is of great significance in the primary prevention of coronary heart disease. In order to fulfill the ever increasing requirements concerning the external appearance, reproducible production of medicines and to decrease the time necessary for the preformulation and formulation experiments, I selected methods which enabled rational experimental design and fast objective evaluation. The objective of my thesis was to formulate tablets containing folic acid, vitamin B6 and B12 of optimal therapeutic concentration and of required stability in the presence of novel excipients applied in direct compression. In the course of my preformulation work thermoanalytical (DTG, DSC), chromatographic (HPLC) and spectrometric (NIR) methods were applied. Destabilizing interactions were evaluated with directly compressible excipients, like Ac-Di-Sol, Cellactose, Tablettose, Avicel PH101, Ludipress. Interactions were detected in the 1 + 1 physical mixtures of vitamins and excipients containing lactose (Cellactose, Ludipress, Tablettose) and their destabilizing effect was confirmed. The results of preformulation studies enabled detection of drug-excipients interactions and selection of compatible excipient system to the given drug composition to formulate dosage form of required stability, processability and effectiveness.

Gonul N et al.,  (2000) investigated the consolidation and compressibility properties and also the dilution potentials of some novel directly compressible filler-binders. For this purpose, Ludipress and Cellastose 80 (one-body compounds), Tablettose 70 and Tablettose 80 (alpha-mono agglomerated lactose) were selected. They were diluted at predetermined percentages with Spherolac 100 which is a coarse sieved hydrous crystalline lactose. The consolidation and compressibility properties of the prepared powder mixtures were determined. The experimental data were evaluated by using a computer programme (Basic 80).
Heinz R et al.,  (2000) using Ludipress greatly simplifies formulation development and the manufacturing process because only the active ingredient Ludipress and a lubricant need to be mixed briefly before being compressed into tablets. The studies described here were designed to investigate the scale-up of Ludipress-based formulations from laboratory to production scale, and to predict changes in tablet properties due to changes in format, compaction pressure, and the use of different tablet presses. It was found that the tensile strength of tablets made of Ludipress increased linearly with compaction pressures up to 300 MPa. It was also independent of the geometry of the tablets (diameter, thickness, shape). It is therefore possible to give an equation with which the compaction pressure required to achieve a given hardness can be calculated for a given tablet form. The equation has to be modified slightly to convert from a single-punch press to a rotary tableting machine. Tablets produced in the rotary machine at the same pressure have a slightly higher tensile strength. The rate of increase in pressure, and therefore the throughput, has no effect on the tensile strength of Ludipress tablets. It is thought that a certain minimum dwell time is responsible for this difference. The production of tablets based on Ludipress can be scaled up from one rotary press to another without problem if the powder mixtures are prepared with the same mixing energy. The tensile strength curve determined for tablets made with Ludipress alone can also be applied to tablets with a small quantity (< 10%) of an active ingredient.
Goto K et al.,  (1999) developed a novel type of multipurpose excipient (MPE) with high binding characteristics and high fluidity. In this study, the capabilities of MPEs (Ludipress and Microcelac) were compared with those of excipients in general use. Also, the effects on powder and tableting characteristics of the physical properties and contents of active ingredients were examined in tablets prepared with these MPEs by the direct compression method. Multipurpose excipients mixed with adjuvants such as fillers, binders, lubricants, disintegrants, and the like show superior fluidity and compressibility. Tablets containing very small amounts of highly active ingredients with little dispersion were prepared. However, with increases in active ingredient content, each of the physical properties was affected strongly by the properties of the active ingredient. Tablets with appropriate hardness and disintegration characteristics could be prepared by mixing of different types of MPEs.
Monedero Perales MD et al.,  (1994) determined the consolidation mechanisms of the lactose-based excipients Fast Flo Lactose, Ludipress, Cellactose and Tablettose. The Leuenberger equation has been modified to obtain values of compressibility and compactability by using a value of compactability obtained from a tablet at maximum applied force and by substituting deformation resistance by relative deformation resistance. Also, parameters obtained from plots of the Heckel tablet-indie and ejected-tablet methods were calculated in order to establish the comparative consolidation mechanisms in the lactose-based excipients under study. The possibility of using the absolute value of the difference between upper and lower surface hardnesses of the tablets made on an eccentric press is suggested as an alternative method to determine the comparative consolidation mechanisms of different substances.

Major challenge for tablet manufacture comes from the powder characteristics of the materials to be compressed. This in turn poses a challenge in achieving greater productivity and better quality product especially on the new generation high-speed machines. The conventional method of wet granulation has inherent drawbacks in terms of achieving batch-to-batch reproducibility and higher productivity, especially in low particle size range. Compared t wet granulation, direct compression requires fewer processing steps, offers simplified validation and results in product with better stability. Advancement in direct compression technology has come in the form of directly compressible co-processed excipients as a problem solver. The present study evaluates and characterizes two different spray dried co-processed materials, one comprising lactose, crospovidone, and povidone and the other composed of lactose and povidone. In this study, the capabilities of multipurpose excipients (MPEs) were compared with lactose. Also, the effects on powder and tableting characteristics of the physical properties and contents of active ingredients were examined in tablets prepared with these MPEs by direct compression method. Prototype tablet formulations were developed with these co-processed materials using acetazolamise as a poorly compressible drug and metformin HCl as a hygroscopic drug. Their performance was compared vis-à-vis conventionally processed tablet formulations. 
The following materials that were either AR/LR grade or the best possible grade were used as supplied by the manufacturer without further purification or investigation.

No.Materials UsedGrade   Supplier
1.AcetazolamideB.P.Zydus Cadila pharmaceutical Ltd., Ahmedabad.
2.Metformin  HCLB.P.Zydus Cadila pharmaceutical Ltd., Ahmedabad.
3.LudipressUSPBASF, Germany.
4.Ludipress LCEUSPBASF, Germany.
5.TalcA.R.Adelphi Labs. Ltd. 
6.Magnesium stearateA.R.Adelphi Labs Ltd.

The following equipments were used in the present work:
No.EquipmentsCompany / Supplier
1.Electric balanceShimadzu, Japan.
2.Rotap sieve shakerPritec.A.C. Induction motor  Gurprit elc.Co.
3.U.V.SpectrophotometerU.V.1201 , Shimadzu, Japan.
4.Tablet Punchig machineRoyal artist, Mumbai.
5.Dial caliperMituoya, Japan.
6.Hardness testerMonsento.
8.Disintigration  ApparatusElectrolab, model ED 2, India.
9.Dissolution ApparatusElectrolab,dissolution apparatus,USP  XXIII

       HCL (PH-1.2) 
1.An accurately weighted 100 mg of acetazolamide was dissolved in 100 ml of 0.1N HCI (PH 1.2) to get 1 mg/ml solution.
2.From this solution, pipette out 10 ml of solution in 100 ml volumetric flask & volume is adjusted to 100 ml to get 100 µg/ml.
3.From this stock solution, aliquot of 0.1, 0.2, 0.4, 0.6, 0.8, 1, 1.2, 1.4l, 1.6, 1.8, 2l ml were pipette out in different 10 ml volumetric flask & volume is adjusted to 10 ml.
4.The absorbance of different solution was measured at 266 nm using U.V. spectrophotometer against respective parent solvent as a blank.
5.The standard curve was obtained by plotting absorbance vs. concentration in µg/ml.
Table 5. Standard calibration curve for Acetazolamide
Concentration (µg/ml)Absorbance at 266 nm.

1. An accurately weighted 100 mg of MetfrminHCL was dissolved in 100 ml of phosphate buffer  (PH 6.8 ) to get 1 mg/ml solution.
2.From this solution, pipette out 10 ml of solution in 100 ml volumetric flask & volume is adjusted to 100 ml to get 100 µg/ml.
3.From this stock solution, aliquot of  2, 4, 8l, 10, 12 ml  were pipette out in different 100ml volumetric flask & volume is adjusted to 100 ml.
4.The absorbence of different solution was measured at 234 nm using U.V. spectrophotometer against respective parent solvent as a blank.
5.The standard curve was obtained by plotting absorbence vs. concentration in µg/ml.

Table 6. Standard calibration curve for Metformin HCl
Concentration (µg/ml)Absorbence  at  234 nm.

5.2.1 Particle size distribution 
Particle size distribution Was performed on random samples of all the batching using a nest  of standard sieve such as 30, 44, 60, 85, 100,120, 200 meshes having 590-, 350-, 250-, 177-, 149-, 125-, and 74-µm openings, respectively. The sieves were agitated on a rotap sieve shaker (International Combustion ltd., London) for 5 minutes. From the percentage weight of agglomerates retained on each sieve, the mean agglomerate diameter was calculated.

5.2.2 Percentage fines  
It is defined as the percentage of the agglomerate passed through 200 Mesh. 30/200 sieve fraction was used for further evaluation.  The % yield, mean particle size and percentage fines are recorded.

5.2.3 Angle of repose.
 Enar Reposograph 640 (Enar Foundation Research Center, India) was used for determining angle of repose. 25gm sample was used for the test and the sample was graded as excellent, good, fair or poor if the value of angle of repose was found to be 30-32o, 33-35o, 36-37o or 38-45o respectively.

5.2.4 Carr’s index
A glass cylinder with 100ml capacity was filled with sample and tapped (500 times) from a height of 2 inches. The value of bulk density and tapped density were calculated. The percentage compressibility was calculated as 100 times the ratio of the difference between tapped density and bulk density to tapped density.
Carr’s index  

5.2.5 Hausner Ratio 
A glass cylinder with 100ml capacity was field with sample and tapped (500 times) from a height of 2cms. The value of Hausner ratio was calculated as,

Hausner Ratio   

5.2.6 Volume flowability 
 A Glass funnel as described in the British Pharmacopoeia’s flow ability test was fixed in a strictly vertical position. The bottom opening was blocked by a plastic stick and then 30gm of product was introduced carefully into the dry funnel in order to avoid dusting and compaction. The funnel was unblocked and the time the entire powder needed to flow out of the funnel was measured (n=3). Flow ability was expressed in seconds per 100gm of sample.

Table 7. Standard indication of material
IndicationAngle of repose  Carr ,s Index Hausner’s Ratio
Excellent        25 - 30        1 – 10          1 - 1.11
Good        31 - 35      11 – 15     1.12 - 1.18
Fair        36 - 40      16 – 20     1.19 - 1.25
Passable        41 - 45        21 - 25     1.26 - 1.34
Poor        46 - 55      26 – 31     1.35 - 1.45
Very poor        56 - 65      32 – 37     1.46 - 1.59
Very very  poor          >65        >38          >1.60

5.2.7 Kawakita’s and Ludde’s equation. 
The packability was evaluated by tapping the agglomerates in a measuring cylinder. The data were analyzed by using Kawakita’s and Ludde’s equation 1, 2, 3. Respectively, where a and b = constant; n= Tap number; and Vo, Vn and Vinf =powder bed volumes at initial, after nth tapping and at equilibrium state, respectively. 
In this method, agglomerates/granules was filled in 50ml capacity measuring cylinder was tapped from a height of 2 inches. The volume of the  100, 200, 300, 400 and 500 taps. The slope was obtained from the plot between ratios of number of taps. The reciprocal of slope gave the value of Kawakita’s constant ‘a’ and from the value intercept and ‘a’, the value of ‘b’ was calculated:

         …… (1)
       ……  (2)
       …….. (3)

5.2.8 Kuno’s equation 
It is Similar experimental observation can be used to calculate Kuno’s constant ‘k’ by equation 4 as follows:
ρf   =  ρn  =  (ρf  -  ρo) e(-kn)  .…..(4)

Where, ρf, ρn, ρo = apparent densities at initial state: after nth tapping (5, 10, 15, 20,                                                25, 50, 75, 100, 200, 300, 400); and at equilibrium (500th tap) respectively. k= constant.

5.2.9. Moisture uptake
A 5-gm sample of Ludipress and Ludipress LCE were separately spread uniformly in a 5 cm diameter petridish, and the dish was stored at 75% relative humidity at 45°C in a dessicator. The percentage increase in weight was noted after 24 hrs.

Conventional tablets were prepared by direct compression method. Other excipients were Ludipress &/or Luipress LCE, Talc & Magnesium stearate. For preparation of tablet, drug was accurately; mix thoroughly with other excipients by geometrical mixing method. The resultant mixture was compressed into tablet using a single punch machine (Royal artist, Mumbai), 10 mm die and punches were adjusted as a weight of each tablet and hardness between 3-5 kg/cm2. The formula for various formulations attempted has been given in table.
Table 8. Preparation of Acetazolamide tablet (mg)
Batch CodeA1 A2 A3 A4 A5 A6 
Table wt.(mg)300300300300300300
All the batches contains Ludipress LCE in batch A7 to A12
Table 9. Preparation of Metformin HCl tablet (mg)
Batch CodeM1M2M3M4 M5 
Table wt.(mg)300300300300300
All the batches contains Ludipress LCE in batch M6 to M10
5.4.1 Tablet Dimension
Thickness and diameter was measured using a calibration dial caliper. ten tablet of each batch is calculated.

5.4.2 Hardness
Monsento hardness taster was used to evaluate hardness of tablet. The taster consists of a barrel containing a compressible spring held between two plungers. The lower plunger was placed in contact with the tablet, and a zero reading was taken. The upper plunger was then forced aginst a spring by turning a thread bold until the tablet fractures. As the force of fracture was recorded, and the zero force was deducted from it. Ten tablet of each batch were evaluated.   
5.4.3 Tensile strength 
The dimensions of tablets were measured by using a micrometer. The hardness of the tablets was determined after 24 hrs of compression (time for stress relaxations of compression) by using Monsanto hardness tester (Shital Scientific Industries, Mumbai). From the values of diameter D (cm), thickness L (cm) and hardness P (kg); the tensile strength (MPa) of the tablets was calculated by using Equation 5 as follows
                                       T        ……(5)
5.4.4 Friability 
Friability was evaluated as the percentage weight loss of 20 tablets in a friabilator (model EF2; Electrolab, Mumbai) for 4 minutes at 25rpm. The tablets were then dedusted and the loss in weight caused by fracture or abrasion was recorded as percentage friability.
                                      F      …..(6)
Where, F is percentage friability, Wo is initial weight of tablets and W is final weight of tablet
5.4.5 Weight Variation.
Twenty tablets randomly used, witch were weighed individualy and average was calculated. Then deviation of each tablet from average weight was calculated and percent deviation was computed.standard deviation was compired with the U.S.P. limits.
Table 9. USP Limits
Average weight of tabletsPercentage deviation
132 mg or less10
132 mg to 324 mg7.5
324 mg or more5.0
5.4.6 Lubricant Sensitivity Ratio 
Lubricant Sensitivity Ratio (LSR) is used as a quantitative measure to express sensitivity of tableting materials (strength reduction) for lubricant. Agglomerates of Ludipress, Ludipress LCE and magnesium stearate were mixed in 99:1 proportion and compressed into tablets. The lubricant sensitivity ratio was evaluated as per following Equation 7.
        ……… (7)
Where, TS(u) and TS(l) is a tensile strength of unlubricated and lubricated tablets respectively.

5.4.7 Dilution Potential Study
Dilution potential or dilution capacity is a measure of the proportion of poorly compactable drug, which can be incorporated into a vehicle to produce satisfactory tablets. Dilution potential is assessed by comparing the hardness versus compaction force curves for various binary mixtures of the filler and poorly compactable substance. Many active ingredients are poorly compressible in either their crystalline or their amorphous forms. Thus in choosing a vehicle it is necessary to consider the dilution potential of the major filler binder. It is not possible to give specific values for the each filler because the dilution potential depends upon the properties of the drug itself.
Acetazolamide and Metformin HCl have been used as a model drug for the measurement of dilution potential. The poor tableting property of Acetazolamide is very well known to those good at the art. It is very difficult to produce tablets with high content of drug because of Acetazolamide is a high dose, poorly compressible drug . Metformin HCl is a high dose, poorly flowing and hygroscopic in nature . Directly compressible diluents (Ludipress and Ludipress LCE) or the physical blend of the ingredients was blended with drug for 5 min. The powder was blended with the tableting aids like maize starch, saccharin, talc, and magnesium stearate. The powder mixture was tableted using Rotary Tablet machine (Cadmech Machinery Ltd., Ahmedabad), fitted with 10-mm flat-faced punches. The average weight of tablets was 300 mg. The tablets were evaluated for tensile strength, friability, and disintegration time.
Table 10. Composition and results for dilution potential study.
IngredientBatch Code
Lactose (Physical mixture)-----261
Mg. Stearate333333
Total Weight (mg)300±16300±12300±11300±14300±09300±15
Tensile  Strength (MPa)1.1641.1481.1020.9940.4080.814
Friability (%)0.1340.6020.7420.8035.0082.13
Disintegration Time (min)7.476.55.24.85

Table 11. Composition and results for dilution potential study.
IngredientBatch Code
Ludipress LCE261231201171141-
Lactose (Physical mixture)-----261
Mg. Stearate333333
Total Weight (mg)300±16300±10300±12300±15300±08300±13
Tensile  Strength (MPa)1.1781.1531.1381.0020.3080.732
Friability (%)0.112 0.5810.6450.7824.8912.53
Disintegration Time (min)
5.4.8 Disintegration time 
The time required for disintegration of six tablets placed in each tube of disintegration test apparatus (model ED2; Electrolab, Mumbai), was measured at 37+1oC using 900ml distilled water.

5.4.9 In-vitro drug release study 
The method Specified in U.S.P as drug release test was followed.
Tablet was placed in round bottomed flask of apparatus containing 900 ml of dissolution medium. Assembly was set up as per requirement & condition was maintained as per USP. Samples were withdrawn at 0, 10, 20, & 30 min. After each withdrawal, 10 ml of fresh dissolution medium was replaced at the same time. The absorbance of withdrawn samples, after suitable dilution was measured at appropriate λmax against appropriate buffer blanks.       
Table 12. Conditions for in-vitro drug release study
Tablet usedAcetazolamideMetforminHCL
U.S.P. Apparatus used U.S.P.Appratus-II
(paddle type)U.S.P.Appratus-II
(paddle type)
Dissolution medium0.1N HCL (pH-1.2)Phosphate buffer (pH-6.8)
Temperature37 ± 0.5 oC37 ± 0.5 oC
λmax265 nm235 nm

All the formulations were subjected to evaluation parameters such as thickness, diameter, friability, weight variation, and in-vitro dissolution study. The results of all the formulation was satisfied with predetermined objects and results were shown in the tabulated as well as graphical manner.

6.1 Standard Calibration curve of model drug.
Table no. 5 & 6 shows the absorbance readings of Acetazolamide & Metformin HCL  respectively. Same way Figure 1 & 2 represents the standard calibration curve of Acetazolamide & Metformin HCL. The equation & value of R2 is given bellow.
- Acetazolamide:
                             y = 20.69x – 0.3830
                            R2 = 0.9950
        - Metformin HCL:
                                    y = 0.0783x + 0.033
                                    R2= 0.9962

6.2 Physical Characterization of Excipients.
6.2.1 Angle of repose, Hausner ,s ratio, Carr ,s Index, & Flowability.
Angle of respose of both the marketed product was less than 32° indicated good flow property. In case of compressibility index the both the material were exhibited excellent compression characteristics (CI < 12 %). Hausener ratio of both the product are less than 1.14 indicating good and  acceptable property (HR < 1.14)

Table 11. Results of physical parameters
Material    Ludipress   Ludipress LCE
Angle of Repose ( o )     30.76      31.24
Bulk Density (gm / ml)       0.52        0.51
Tapped Density(gm /ml)       0.58        0.58
Carr ,s Index ( % )     10.34      12.06
Haussner ,s Ratio       1.11        1.13
Flow Time (sec.)       5.16        6.1

6.2.2 Particle Size Analysis.
The agglomerates of Ludipress and Ludipress LCE were analyzed by rotap sieve shaker, the results revealed that all the agglomerates of both the marketed product were passed through sieve 22 mesh (710 µm), not >20 % passed through 120 mesh (125 µm), and almost all the agglomerates retained on 200 mesh (74 µm). As per the analysis the mean particle size of Ludipress agglomerates was found 178.65 µm and Ludipress LCE was found 195.32 µm (Table 12). The scanning electron photograph of both the marketed product is depicted in Figure 4a and 4b. 

 Table 12. Results of particle size analysis study (n=1)
Standard SieveSize reduced (B1-B2) µm.Arithmatic mean.             
Wt.retained       (d) gm.
% retained  (E)

Wt. Size        (F= C x E)

Ludi.LCE   Ludi.   LCELudiLCE

6.2.3 Packability testing 
The packability of samples were ascertained by comparing the constants a, b, and k, in Kawakita’s and Kuno’s equations, respectively (Table 13). The constant “a” represents the proportion of consolidation as closest packing is attained. The reciprocal of “b” and “k” represent the packing velocity. The constant “a” for the Ludipress (0.100) was smaller than for the Ludipress LCE. The result indicates that the agglomerates of Ludipress show good packing even without tapping. The larger value of “b” for the agglomerates of Ludipress (0.0928) proved that the packing velocity of the Ludipress was faster than the Ludipress LCE. The “k” for Ludipress was found 0.0049. The smaller value of k in the Kuno’s equation supports the above findings. The slow packing velocity corresponds with proportion of the consolidation of the powder bed per tap. The kawakita plot of Ludipress LCE and Ludipress represent in Figure 5. Ludipress is the co-processed multifunctional product, consists of 93.4 % α-lactose monohydrate, 3.2 % polyvinyl pyrrolidone (Kollidon 30) and 3.4 % crospovidone (Kollidon CL). The agglomerates of Ludipress showed good compression property compared with other samples. 
Table 13. Results of packability testing
SampleKawakita’s Constant “a”Kawakita’s Constant “b”Kuno’s Constant “k”
Ludipress® LCE0.1120.05050.0081
6.2.4 Moisture Uptake study
After 24 hr storage at 75 % relative humidity and 45˚C, agglomerates of Ludipress and Ludipress LCE adsorbed 11 % w/w and 14 % w/w moisture. This may be due to the adsorptive nature of the PVP . The results revealed that the material is slightly sensitive to moisture so, should be preserved in tightly closed container.
6.3   Evaluation of Tablet
6.3.1 Tablet dimension and Hardness:
Tablet dimensions include diameter and thickness which was taken  10mm & 3 mm respectively. Three tablets of each batch were evaluated and hardness values were found in range of 3.5 to 6.5 kg/cm2. The results were tabulated in table no.14&15.

Table 14.  Evaluation of   Acetazolamide Tablet.
Batch CodeMean Diameter
(D) mm
Mean Thickness
(L) mmMean Hardness
(P) kg/cm2

Table 15. Evaluation of MetforminHCL
Batch CodeMean Diameter
(D) mm ,             
Mean Thickness
(L) mm.              
Mean Hardness
(P) kg/cm2   


6.3.2 Friability:
Friability test was carried out as per standard method given in USP.. These values are with in the acceptable limit (< 1%), implies good compactness and strength of each formulation. The results were tabulated in table no.16 & 17.

6.3.4  Tensile Strength:
Tensile Strength  >0.85 was selected as the selection criterion for the formulation. Almost all batches exhibit satisfactory Tensile strength. The results were tabulated in table no.16 & 17.

6.3.5  Disintegration time:
The disintegration time depends on the tensile strength of  tablet. The disintegration time of each formulation is mentioned in table no.16 & 17. Disintegration time of Ludipress containing tablet is between 0.49 to 1.09 minute while Ludipress LCE containing tablet having 9.48 to 12.01 minute shows that the Ludipress containg tablet disintegrate faster then the Ludipress LCE containing tablet because of presence of super disintegrant. 
  Table 16:  Evaluation of   Acetazolamide Tablet.
Batch CodeFriability (%)
    Tensile strength (Mpa)
Disintegration time (min)

Ludi.         LCELudi.         LCELudi.         LCE

Table 17:  Evaluation of   MetforminHCL Tablet.
Batch CodeFriability
(F) % ,   Tensile strength
Disintegration time

Ludi.       LCELudi.       LCELudi.       LCE

6.3.7 Lubication Sensitivity Test.
The addition of magnesium stearate decreases the tensile strength of tablets. It is well known that prolonged mixing of magnesium stearate produces film around the agglomerates and prevents the agglomerates from binding. The effect is more pronounced in the case of plastically deforming material than for material undergoing brittle fracture. In light of these arguments and from the data shown in Table 18 and 19, one can conclude that prolonged mixing of magnesium stearate decreases the tensile strength of tablets. Lubricant sensitivity ratio is a quantitative measure to express with a lubricant: the greater the lubricant sensitivity ratio, the more the susceptibility to mix with a lubricant. Mixing time exhibits a greater effect on tensile strength as compared with the effect of compression time. Hence, one may conclude that both the agglomerates (Ludipress and Ludipress LCE) are sensitive to lubricant.
Table 18. Effect of magnesium stearate on Ludipress agglomerates
Ludipress (%)10099999999
Magnesium stearate (%)-1111
Mixing time (min)-111010
Compression time (sec)1130130
Hardness (kg/cm2)
Tensile Strength (MPa)2.452.102.381.821.98
Lubricant Sensitivity Ratio (%)-0.1420.0280.2570.191

Table 19. Effect of magnesium stearate on Ludipress LCE agglomerates
Ludipress LCE (%)10099999999
Magnesium stearate (%)-1111
Mixing time (min)-111010
Compression time (sec)1130130
Hardness (kg/cm2)8.788.588.8
Tensile Strength (MPa)2.342.012.291.841.95
Lubricant Sensitivity Ratio (%)-0.1410.0210.2130.166

6.3.8. Dilution Potential Study
Tablets were prepared using 10-50% acetazolamide. The authors arbitrarily decided to select a batch that showed a friability value < 1 and tensile strength tensile strength > 0.85 MPa. From the results shown in Table 3and 4, it is quite evident that 40% acetazolamide produces acceptable tablets with both the marketed adjuvants (Ludipress and Ludipress LCE). As the percentage of acetazolamide was increased, the tensile strength decreased (Figure 6 and 7). This result might be caused by the poor compressibility and elastic recovery of acetazolamide which also affects the percent friability and disintegration time. Physical mixture having same composition did not yield satisfactory tablets with 10 % acetazolamide. This results shows that agglomerates of Ludipress and Ludipress LCE exhibited higher compressibility and better binding property than the other batches. Disintegration time of batch LA to LF compared with the batch LEA to LEF, the results revealed that Ludipress agglomerates also decreases the disintegration time of acetazolamide tablet then the Ludipress LCE tablets. For the metformin HCl drug the dilution potential capacity of both the marketed product was found 50 %. 

6.3.9   In-vitro Drug release study
In the In vitro drug release study of Acetazolamide and Metformine HCl the results obtained are mentioned in Table 21 & 22. The drug release of Acetazolamide is 98.23 %  with the Ludipress and 95.77 % with Ludipress LCE. The Ludipress containing tablets shows faster drug release than the tablet containing Ludipress LCE, because Ludipress contains the  cross povidon as a super disintigrater  which increase the disintigration rate.

   Table 20. Information of the marketed tablets.   
Durg NameAcetazolamideMetforminHCL
Brand NameDiamox.Glycomate.
Dose250 mg.500 mg.
Batch No.DIM. 11733000037
Mfg. CompanyMedreich  Ltd.USV.  Ltd.

Table 21: In-vitro drug release study of Acetazolamide Tablet.
Time (min.)AbsorbancePercentage  CPR

MarketedTablets.Prepared tablets with LudipressPrepared tablets with Ludipress LCEMarketed tabletsPrepared tablets with  LudipressPrepared tablets with Ludipress LCE

Table 22: In-vitro drug release study of Metformin HCl
Time (min.)Absorbance  
%  CPR

Marketed tabletsPrepared tablets with LudipressPrepared tablets with Ludipress LCEMarketed tabletsPrepared tablets with LudipressPrepared tablets with Ludipress LCE

Commercially available different grade of lactose has the required directly compressible characteristics but it fails to provide the desire disintegration and dilution properties required for tablets. Ludipress  LCE (BASF Pharmaceuticals, Germany) is a commercially available spray dried co-processed product comprising of 96.5% lactose monohydrate and 3.5% povidone  having better flow and compressibility but lacking in disintegration ability and suspendibility. As compred to it, the investigated co-processed excipient additionally contain crospovidone (3.4 %) which is proven superdisintegrant. Incorporation of this imparted property of disintegrability and suspendibility to co-processed excipent.
In summary, a co-processed adjuvant containing built in superdisintegrant can be used as a potential multipurpose excipient. Clearly from the results of this study, physical modification of lactose monohydrate resulted in considerable improvement in its functionality as a directly compressible filler. These materials can be ideal choice for making, tablets containing medium dose medicament having poor compression characteristics and hygroscopic drug by direct compression technique, as well as dispersible tablet with low dispersion time at high tablet hardness and tensile strength. They can also be a good substitute for inert/dummy granules, which are normally used in tablet manufacturing.

1.Sam, A.P., Fokkens, J.G., Drug Delivery System, Adding Therapeutic and Economic value to Pharmacotherapy, Pharm. Tech. Eur.1997; 9: 58-66. 
2.Rasenack N, Muller BW. Crystal Habit and Tableting Behaviour. Int.. J. Pharm.2002; 244: 45-57.
3.Khan KA, Rhodes CT. The Production of Tablets by Direct Compression, Can. J.  Pharm. Sci.1973; 8: 1-5.   
4. Shangraw RF, Demarets DA. Survey of Current Particles in the Formulation and Manufacture of tablets and Capsules. Pharm. Technol 1993; 17: 32-44.
5. Robertson MI. Regulatory Issue with Excipients. Int. J. Pharm.1999; 197: 273-276. 
6.Gonnissea Y, Remona  JP, Vervaet C. Pharmaceutical excipient  having  improved compressibility. Europian  J. Pharma. 2007; 67: 220-226.
7. John NS, Bob ES, Edward AH. Pharmaceutical excipieants having improve compressibility. US  Patent  no 5725883. 
8.Uhumwangho MU, Okor RS. Anmolous effect of compression on the brittle fracture of α cellulose tablets. Int. J. Pharma.2004; 284: 69-74.
9.Tsuimin Tasi, Jen-sen Wu, Hsiu-O Ho, Ming thau Sheu. Modification of physical characteristic of microcrystalline cellulose by Co- drying with cyclodextrins. J. Pharma. Sci. 2000; 87: 117-122.
10.Gohel MC, Jogani PD. Development of  agglomerated  directly compressible diluents consisting of  brittle and ductile materials.  Pharma. development and technology 2003; 8: 143-151.
11. Rao AB, Misra AN. Modification of lactose for direct compression II Ind.  J. Pharm. Sci. 1999; 61(4): 231-236.
12. Gohel MC, Jogani PD, Bariya SH. Development of agglomerated  directly compressible diluents consisting of  brittle and ductile materials.  Pharma. development and technology 2003; 8: 143-151. 
 13.Jogani PD. Gohel MC. Preparation and assessment of novel co-processed superdisintigrant consisting of  crosspovidone  and sodium starch glycolate. AAPS Pharm. Sci. Tech. 2005.

14. Sengel- Turk CT, Hascicek, Gonul N, Microsphere-based once-daily modified release matrix tablets for oral administration in angina pectoris, University of Ankara, Tandogan, Ankara, Turkey. 2008; 225(4): 257-266.
15.El-Maradny HA, Modulation of  Pursetile drug delivery system using different swelleble materials, University of Alexandria, Alexandria. 2007; 14(8): 239-246.  
16.Hascicek, Gonul N, Microsphere-based once-daily modified release matrix tablets for oral administration in angina pectoris, University of Ankara, Tandogan, Ankara, Turkey.2006; 23(2): 135-152.
17. Cavallari C, Albertini B, Rodriguez L, Rabasco AM, Fini A. Release of Indomethacin from ultra sound dry granules containing Lactose bsed Excipients. Dipartimento di Scienze Farmaceutiche, Università di Bologna, Italy.Cotrolled release.2005; 102(1): 39-47.
18. Jogani PD. Gohel MC Review of  coprocessed  DC. Excipients. J. Pharm. Sci.2005; 8(1): 76-93. 
19. Mashkura Ashrafi, Jakir Ahmed Chowdhury, Md Selim Reza. Controlled Release of Metformin Hydrochloride I. In vitro Release from Physical Mixture Containing Xanthan Gum as Hydrophilic Rate Retarding Polymer. Dhaka Univ. J. Pharm. Sci. 2005; 4(1): 125-137
20.Kapat. Effects of polymer type, polymer:direct tabletting agent ratio and tabletting method on verapamil, Ankara Ecz. Fak. Derg J. Fac. Pharm. Ankara.2004; 33(3):125-137.
21.Md. Selim Reza, Mohiuddin Abdul Quadir, Syed Shabbir Haider, university of  Dhaka. 2003.
22.  Budavári Z. Formulation of tablets decreasing Plasma homocysteine levels. Semmelweis Egyetem, Gyógyszerészeti Intézet, Budapest, Hógyes Endre u. 7.-1092. Acta Pharm. Hung.2001; 71(4): 433-440.
23. Gonul N. The Consolidation and compressibility Property of some novel directly compressible Binders & fillers. Ankara University, Acta Pol Pharm.2000; 57(4): 311-317.
24. Heinz R, Wolf H, Schuchmann H, End L, Kolter K. Formulation of tablet based on Ludipress and scale up from Lab. Scale. Drug Dev Ind. Pharm.2000; 26(5): 513-521.
25. Goto K, Sunada H, Danjo K, Yonezawa Y.Evaluation of multifunctional Excipients for direct compression. Meijo University, Nagoya, Japan. Drug Dev Ind. Pharm.1999; 25(8): 869-878.
26. Monedero Perales MD, Muñoz-Ruiz A, Velasco Antequera MV, Jiménez-Castellanos Ballesteros MR. Study of compaction mechanism of lactose based  directly compressible Excipients using indentation hardness & Heckel plots. J. Pharm. Pharmacol. 1994; 46(3): 177-181. 
27.Almon CJ, Bravo SA, Lamas MA. J. Pharma. Sci .2002; 5: 213.
28. Parot EL, Lachman L, Liberman  HA, Kanig JL. Eds Lea and febiger. Theory and practice of Industrial Pharmacy.1986; 3: 21-46. 
29.Ozkir A. Kinetic evaluation  mechanical  strength of briquette granules. Drug Dev. Ind. Pharm.1997; 23(6): 589-594.
30. Fiese EF, Hagen TA, Lachman L, Liberman HA, Kaninig JL, Eds Lea and Febiger. Preformulation, Theary and Practise of Industrial Pharmacy.1986; 3: 171-194.  
31.Carr RL. Evaluating flow properties of solids.Chem Eng 1965: 18.
32.Hausner H. Friction conditions  in a mass  of  metal  powder. Int. J. Powder Metal 1967: 3.
33.The British Pharmacopoeia IV. Pharmaceutical Technical Procedures, Appendix XVII-E, Flowability. 2005; 374. 
34.Kawakita K, Ludde KH. Some consideration on powder compression equation. Powder technol.1970; 4: 61-68.
35.Kawashima Y, Okumura M, Takenaka H, kojima A. J. Pharma .Sci.1984; 73: 1535-1538. 
36.  Basu Murali, Mohan GV. Ind J.Pharma. Sci.2002; 37-43: 807.
37.USP.  XXIV-NF   XIX 2000. Asian edition, USP Conention Inc.1941.
38.Shirwaikar AA, SrinathAj. J. Pharma. Sci.2000; 66(4): 433. 
39.Gohel MC, Jgani PD. An  investigation  of the direct compression Characteristics of  Co-processed Lactose –miccrocrystalline. Cellulose using statistical design. Pharma. Technol.1999; 23(11): 54-62  
40. Friability in USP 24-NF 19,  United State Pharmacopeial  convention  Inc. Rockville.2000; 2148.   
 .Bolhuis GK., and Holzer, A,W., Lubricant Sensitivity in Pharmaceutical Powder Compaction Technology, Vol-7. Alderborn, G., and Nystron, C., Eds., Marcel Dekker, USA.1996; 517-560.
 .Gohel MC., Jogani, P. D., and Bariya, S. H., Development of Agglomerated Directly Compressible Diluent Consisting of Brittle and Ductile Materials, Pharm. Dev. Technol. 2003; 8(2):143-151.
 .Gohel MC., and Jogani, P. D., Exploration of Melt Granulation Technique for the Development of Co-processed Directly Compresible Adjuvant Containing Lactose and Microcrystalline Cellulose, Pharm. Dev. Technol., 2003; 8(2):175-185
44. Disintigration Time in USP 24-NF 19, United State Pharmacopeial   convention   Inc. Rockville. 2000 :2148. 
45. Aulton ME., Cellulose Powdered, in Handbook of Pharmaceutical Excipients, Rowe RC., Weller PJ., Eds., The Pharmaceutical Press, UK., 2003; 112-114.

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