Drug Formulation Development - Science topic

AI: The issue you’re encountering — turbidity and crystal formation upon dilution of limonoid aglycone from DMSO stock into aqueous media — is common when working with poorly water‑soluble hydrophobic compounds. Here’s a systematic approach to resolve it:

Root Cause

Limonoid aglycones are highly lipophilic. When you dilute DMSO stock (10 mg/mL) into aqueous cell culture media:

Recommended Solutions

Practical Protocol Example

Key Considerations

By combining solvent optimization, solubilizing agents, and proper handling, you should achieve a stable, homogeneous solution for reliable cytotoxicity testing.

You can try customized molds to fabricate hydrogel microneedles for transdermal drug delivery.Many hydrogels are commercially available.

Of course you will have to perform a QA audit of the new manufacturer's facility, but you could have a limited method validation (which should include specificity, linearity (which you could derive the LOD and LOQ), repeatability... Don't be surprised if the impurity profile is different since it is dependent on the manufacturing process. You should also put the finished drug product that is using the new manufacturer's API, on stability.

There's probably no one recipe for all drugs. I think it's pretty consistent that an amorphous form, if you can obtain it, is more rapidly soluble, and that smaller particles dissolve more quickly (due to the larger surface area), but the other factors will vary from one drug to the next. You don't specify if you're relying on low (slow) solubility for the sustained release effect.

Adam B Shapiro Hi Dr. Shapiro. I've attempted the spectrum scan in the spectrophotometer and the shoulder of the peak appears slightly before 240 nm but the absorbance was > 2.0 even at 0.00125 mg/mL. I believe I have no option but to resort to HPLC as you previously recommended and as reported in previous papers. Thank you so much for your guidance. I am truly grateful for your help.

Kandluri Geethika Thank you for sharing. I shall bear your advice in mind when I conduct the drug release assay.

You can also run an in situ coating at the end of the particle preparation!

As the particle size decreases, Surface area increases , and simultaneously dissolution rate increases. It causes increase in solubility and so more quickly absorbed by the body. As accordingly larger particles have slow dissolution rate and gives sustained release effects.

Intramuscular injections mostly contains insoluble particles in aqueous solvent or soluble particles in non aqueous solvent. Prolonged release also occurs due to other factors like blood supply, drug properties. Larger particles provide maintenance dose.

Dear all, Thanks to Tiffany Tang I am attaching a revised version of the original Excel workbook which contained an error in the calculation of the "%Cumulative Dissolution" (column G). Sorry about the inconvenience,

Regards, Luis

I think yes every formulation should be tested because excipients will be different in each formulation and may lead to increased or decreased bioavailability.

Regards

Thanks Raditya Iswandana for suggestion. I am using Simethicone as antifoaming agent in the formulation but still my final product is foaming upon shaking in bottle.

Michael Fox,

Really appreciate your feedback on this!!

I am able to control the foam during manufacturing by mixing at low speed and applying vacuum during process. But my main concern is foam that is generated on shaking the final product bottle. Please let me know if you have any suggestion on MC phase which doesn't foam on shaking.

Regards

Valsartan is not moisture sensitive. You can use water as a solvent for wet granulation. Do not use hydroxy compound because of the carboxy group of valsartan.

there is the book of the handbook of pharmaceutical excipients

as a galenist, I suppose:

soft capsule shaping contains omega 3 plus other vitamins causes a large capsule therefore it is possible just to administer the liquid contents and discard the gelatinous capsule.

otherwise you have to think about the form:

* separate omega 3 and vitamins (soft capsule + tablets)

* otherwise you will perform tests reducing vitamins to reduce the size of the capsule.

* if possible, try to incorporate some vitamins into the gelatin mass

Good luck

Thank you to All.........

Before all that tests, check the overall cleanliness, any defective polymeric source(s) in the experimentation-storage-processing etc., greasy material presence and, probably degraded or impure raw material- the starting point. The next would be to go to the ionic sources including cationic or anionic (of whatever molecular sizes) in the process steps being generated or already present. If the final product qualifications are literally matching, problem is in media and surrounding material which is producing the white entities. Sudden pH changes are also responsible for these kinds of impurities provided ionic components are being carried in the production.

Thank you.

Histidine has 3 pKas of 1.54, 6.07, and 9.34. The buffer capacity will be best near each pKa. It is relatively easy for me to calculate a specific recipe for a specific pH, but that depends on the presence of all the other buffering agents and salts in solution. The simplest approach for you to take is to add a 5 mM concentration of Histidine (0.077%) and then titrate the pH up or down using HCl or NaOH. I recommend that you pick pH values near the histidine pKas for use if you want good buffer capacity.

In strong acidic conditions (HCl 1N), it should work. Please find attached an article of our research group about this.  

Hi Vipul,

Besides checking Pharmacopeia protocols, find the attached pdfs, where you will get all the details of simulated gastric, intestinal, colonic fluid types, volume, conditions etc. 

For preparation of  Immediate release tablet, Its better to use other hydrophilic binder like PVP, Glucose, acacia, Tragacanth and stach paste.  HPMC will give u lump. Or You can use HPMC by dissolving HMPC in Iso Propyl Alcohol.

I agree with Bruce Neagle.

Before you start the dissolution test, verify the temperature of dissolution medium in vessels.

During a pilot run you can check the temperature before taking sample just to ensure that temperature was remained within the specified range throughout the experiment.

I guess you're hoping to develop a method that is reflective of the invivo performance of your tablet.  I don't believe there is any mandatory requirement preventing you having a floating tablet method if you can present a scientific rationale to justify the deviation from standard method and can document validation of your method.  As Luis said though, you will probably find quite variable release with a floating tablet (making validation difficult) and as Kah suggests, a floating tablet may not actually be particularly reflective of invivo behaviour either. You could use sinkers or basket apparatus.

best way is dialysis.

This condition generally arises if fixed dose combination consists of both weakly acidic and weakly basic compound. Now, here weakly basic dissolved in 0.1NHCL and weakly acidic in basic phosphate buffer. So during dissolution first 0.1NHCL should be used and then phosphate buffer (6.8/7.5). Finally, the calculation can be done by using simultaneous equation.

Equation for the simultaneous equation is very well written in Bentley and stenlake.

According to USP,  For oral formulations dissolution should be performed in a medium having pH range 1.2 - 6.5 and to 7.5 only for modified release substance. For poorly soluble drug, medium may contain a percentage of a surfactant (1% w/v) (polysorbate 80, SLS or lauryl dimethyl amine oxide). The medium should be deaerated by heating, filtration or by applying vacuum.  The sink condition must be maintained for which the quantity of dissolution should not be less than 3 times that required to form a saturated solution of the drug substance and if required volume of the medium can be raised to 2L or 4L using large vessels. For Reference

For Reference Please refer USP

Kindly check these references:-

(1) Sun et al., 2012

Effect of particle size on solubility, dissolution rate, and oral bioavailability: evaluation using coenzyme Q10 as naked nanocrystals

(2) Chu et al., 2012

Effect of particle size on the dissolution behaviors of poorly water-soluble drugs

(3) Tromelin et al., 2008

Relationship Between Particle Size and Dissolution Rate of Bulk Powders and Sieving Characterized Fractions of two Qualities of Orthoboric Acid

(4) Buckton and Beezer, 1992

The relationship between particle size and solubility

 

I recommend keeping a close focus on your pH as you formulate as Dignesh has pointed out. Inclusion of glycerol in the aqueous gel may also help to stabilize your gel behavior. I would recommend an experiment to assess the impact of various pH levels on viscosity and the impact of glycerol. When deciding on pH levels to test, consider the pH and salt composition of the physiological system that will be encountered upon administration.

Hi Ahmed,

I'm guessing that you used dynamic light scattering (DLS) e.g. the Malvern Zetasizer Nano system to measure size? If so, the result you get for size is the 'Z-average' or 'Cumulants mean' and the programme also gives you a PDI value. For the projects that I have been involved in, we were happy with PDI values well below 1 (usually <0.2 for polymeric nanoparticles and liposomes).  

The PDI essentially informs you about how broad your size distribution is, as measured by intensity of scattered light. A broad distribution means that you have larger size variations. As the value of the PDI gets closer to 1, your size distribution gets broader (you would call your system polydisperse i.e. with a broad distributions and probably multimodal, i.e. with more than one peaks/ populations of particles). A high PDI value can also imply that your particles aggregate. Measuring zeta potential might help you with that. PDI<0.1 means that your system can be considered monodisperse (narrow distribution) and monomodal (one peak/population). Depending on the type of the particle, this can be hard to achieve and we're usually ok with slightly higher values. It would be good to compare the results you get from other techniques too as the DLS works best for spherical particles with narrow distributions. You could also check that your dispersant is appropriate for your particles (e.g. does it contain salt?). The Malvern manual is a good starting point for definitions and ways to improve your measurement:

http://www.biophysics.bioc.cam.ac.uk/files/Zetasizer_Nano_user_manual_Man0317-1.1.pdf 

Any paper on nanoformulations including liposomes, PLGA/PLA particles or inorganic particles will give you information on size measuring techniques. DLS is a very reliable one, especially for liposomes which don't look great under the electron microscope (usually TEM). Malvern notes that for PDIs above 0.5, it is not advisable to compare size distributions between different techniques. It's also good to keep in mind that in a broad distribution, your peak is likely to be skewed toward larger sizes as larger particles induce more light scattering therefore a small number of those will contribute more to your distribution. You can get some clue if that's the case by looking at the size distribution by number rather than by intensity (although it is derived from the intensity values).

Hope this helps. All the best with your project.

Regards,

Irini

You can isolate nuclear proteins by first isolating the nuclei only (separating nuclei from cytosol) and then extract the nuclear protein with buffer containing high concentration of salt (NaCl or KCl up to 1 M). You need to know the chemical nature of your drug as well, to know if or how the binding of you drug can be/is affected by the component of buffer you are using.

Please check the particle size of each ingredient I believe that they shall be close

Hi Mahendra,

Try to incorporate super disintegrants in your tablet system such as Crosslinked cellulose derivatives (Crosscarmellose®, Ac-Di-Sol®, Primellose® Vivasol) or Crosslinked PVP derivatives (Crosspovidone, Kollidon, Polyplasdone), use in 1-5% weight ratios to tablet weight. or the following articles might help in other ways https://www.ncbi.nlm.nih.gov/pubmed/18379117. All the best..

I would study, first of all, products of degradation of disoproxil fumarate to take a decision about its stabilisation.  probably its necessary  to reduce the content of water in the granulation, if  products of degradation of disoproxil fumarate are product of its hydrolysis

I think you want to compare improvement in permeation between naproxen powder and its nano particle. 

If drug is lipophilic it means its absorption across the intestinal membrane is dependent on its solubility in aqueous media. Because it will start its permeation only after its dissolution. 

So, I suggest you to try Simulated intestinal fluid with surfactants that might help to dissolve drug and you can compare.

One more thing. You should also compare flux.

My answer is base on what i understand from your question. 

How are you preparing your nanoparticles? Have you consider a change in the crystalline form of the API - this would definitely affect the solubility of the drug, being aligned with the results you mention. 

Other issues, regarding the analytical method itself, like filter compatibility, selectivity of the UV method - were those accounted for also? What dissolution media are you using?

Thank you both Mr. Himangshu Bhatt Mr. Ahmed Agiba for reply.

I think you may add β-Cyclodextrin, as additive. it increases the aqueous solubility of  poorly water soluble drugs.

Dear Abdeen,

As I understood from your problem, you are trying to increase the solubility of your drug, which has low water solubility. There are some other methods also to prepare the fast dissolving tablets. So, you can try with other methods.

If want to use this particular method only then change the base as other researchers have specified in their suggestions.

You may want to consider this paper and see if it helps.

There is one thing what I have forgot to mention. microCT is pretty sensitive to the sample size, since its resolution depends on the sample-X-ray source distance. I the apparatus I have used before the best resolution could be achived only if the sample diameter is not bigger than approx. 3-4 mm. Nevertheless, there are newer  apparatueses available on the market now.

Regards

Tamás

Brennan,

Thank you for the insightful response. I will check out the referenced blog.

I got a chuckle out of the term "pharmacodynamic promiscuity"; that's pretty good.

Thanks,

Chris

Thank you very much Saiesh, I will try this way, best regards, Naiví

If liposomes are the so called alpha and beta lipoproteins, you may isolate them directly from the serum by heparin or phosphotunstate precipitation in the presence of divalent cations (See my fifty years old papers available on Research Gate). The precipitates dissolve when diluted with water and allow the recovery of concentrated lipoprotein solutions.

Dear Sandeep,

please check the saturation solubility of the drug...

use crystallization inhibitors (like HPMC, PVP, HPMCAS ...) and optimize the concentration of crystallization inhibitors.

Regards,

Jagadish K.R

Dear Elvis,

I would like to know if I draw a ligand with MarvinSketch, can I directly use the software in either autodocktools/PyRx or I am required to optimize the ligand but I do not have the HyperChem software which is introduced by my colleague.

I am trying to dock a ligand into a protein with iron but I could not find see the interaction of the ligand with the metal and the protein. I am trying on 2g1m to know whether did my methods work.

Thank you.

Try by spending in a liquid and adding through a tubing via funnel. May get you good result...

No. You will place your nanoparticles in dialysis membrane available in the form of tubes and cassets. These nanoparticles filled systems will be placed in dissolution medium. If you place nanoparticles directly into disssolution medium, they will get removed when you take samples.

These are two examples. Please ask you supplier to find best options.

Symptoms of poor magnesium intake can include muscle cramps, facial tics, poor sleep, and chronic pain. It pays to ensure that you get adequate magnesium before signs of deficiency occur.

But how can you know whether you’re getting enough?

According to population studies of average magnesium intake, there’s a good chance that you’re not.

Less than 30% of U.S. adults consume the Recommended Daily Allowance (RDA) of magnesium. And nearly 20% get only half of the magnesium they need daily to remain healthy.

One method of assessing your magnesium status is to simply contact your health care provider and request detailed magnesium testing. Yet magnesium assessment is typically done using blood serum testing, and these tests can be misleading. Only 1% of magnesium in the body is actually found in blood, and only .3% is found in blood serum, so clinical blood serum testing may not successfully identify magnesium deficiency.

What to do?

Fortunately, it’s possible to get a sense of where your intake may lie simply by asking yourself a few questions about your lifestyle, and watching for certain signs and signals of low magnesium levels.

Learn how to read your signs below, and find out what you can do to ensure magnesium balance and good health. If you answer yes to any of the following questions, you may be at risk for low magnesium intake.

1. Do you drink carbonated beverages on a regular basis?

Most dark colored sodas contain phosphates. These substances actually bind with magnesium inside the digestive tract, rendering it unavailable to the body. So even if you are eating a balanced diet, by drinking soda with your meals you are flushing magnesium out of your system.4 5 6

The average consumption of carbonated beverages today is more than ten times what it was in 1940.7This skyrocketing increase is responsible for both reduced magnesium and calcium availability in the body.8 9

2. Do you regularly eat pastries, cakes, desserts, candies or other sweet foods?

Refined sugar is not only a zero magnesium product but it also causes the body to excrete magnesium through the kidneys. The process of producing refined sugar from sugar cane removes molasses, stripping the magnesium content entirely.

And sugar does not simply serve to reduce magnesium levels. Sweet foods are known by nutritionists as “anti-nutrients”. Anti-nutrients like sweets are foods that replace whole nutritious foods in the diet, yet actually consume nutrients when digested, resulting in a net loss. Because all foods require vitamins and minerals to be consumed in order to power the process of digestion, it’s important to choose foods that “put back” vital nutrients, and then some.

The more sweet foods and processed baked goods you have in your diet, the more likely you are deficient in magnesium and other vital nutrients.

3. Do you experience a lot of stress in your life, or have you recently had a major medical procedure such as surgery?

Both physical and emotional stress can be a cause of magnesium deficiency.

Stress can be a cause of magnesium deficiency, and a lack of magnesium tends to magnify the stress reaction, worsening the problem. In studies, adrenaline and cortisol, byproducts of the “fight or flight” reaction associated with stress and anxiety, were associated with decreased magnesium.4

Because stressful conditions require more magnesium use by the body, all such conditions may lead to deficiency, including both psychological and physical forms of stress such as surgery, burns, and chronic disease.

4. Do you drink coffee, tea, or other caffeinated drinks daily?

Magnesium levels are controlled in the body in large part by the kidneys, which filter and excrete excess magnesium and other minerals. But caffeine causes the kidneys to release extra magnesium regardless of body status.

If you drink caffeinated beverages such as coffee, tea and soda regularly, your risk for magnesium deficiency is increased.

5. Do you take a diuretic, heart medication, asthma medication, birth control pills or estrogen replacement therapy?

The effects of certain drugs have been shown to reduce magnesium levels in the body by increasing magnesium loss through excretion by the kidneys.

See also:

For a complete list of the specific drugs which can affect magnesium levels, read our article, Causes of a Lack of Magnesium.

6. Do you drink more than seven alcoholic beverages per week?

The effect of alcohol on magnesium levels is similar to the effect of diuretics: it lowers magnesium available to the cells by increasing the excretion of magnesium by the kidneys. In studies, clinical magnesium deficiency was found in 30% of alcoholics.10

Increased alcohol intake also contributes to decreased efficiency of the digestive system, as well as Vitamin D deficiency, both of which can contribute to low magnesium levels.11

7. Do you take calcium supplements without magnesium or calcium supplements with magnesium in less than a 1:1 ratio?

Studies have shown that when magnesium intake is low, calcium supplementation may reduce magnesium absorption and retention.12 13 14 And, whereas calcium supplementation can have negative effects on magnesium levels, magnesium supplementation actually improves the body’s use of calcium.7

Though many reports suggest taking calcium to magnesium in a 2:1 ratio, this figure is largely arbitrary. The ideal ratio for any individual will vary depending on current conditions as well as risk factors for deficiency.

However, several researchers now support a 1:1 calcium to magnesium ratio for improved bone support and reduced risk of disease. This is due not only to the increased evidence pointing to widespread magnesium deficiency, but also concerns over the risk of arterial calcification when low magnesium stores are coupled with high calcium intake.

According to noted magnesium researcher Mildred Seelig:

The body tends to retain calcium when in a magnesium-deficient state. Extra calcium intake at such a time could cause an abnormal rise of calcium levels inside the cells, including the cells of the heart and blood vessels… Given the delicate balance necessary between calcium and magnesium in the cells, it is best to be sure magnesium is adequate if you are taking calcium supplements.”8

8. Do you experience any of the following:

Anxiety?

Times of hyperactivity?

Difficulty getting to sleep?

Difficulty staying asleep?

The above symptoms may be neurological signs of magnesium deficiency. Adequate magnesium is necessary for nerve conduction and is also associated with electrolyte imbalances that affect the nervous system. Low magnesium is also associated with personality changes and sometimes depression.

Read more:

For a complete list of the signs of magnesium deficiency, read our article, Symptoms of Low Magnesium.

9. Do you experience any of the following:

Painful muscle spasms?

Muscle cramping?

Fibromyalgia?

Facial tics?

Eye twitches, or involuntary eye movements?

Neuromuscular symptoms such as these are among the classic signs of a potential magnesium deficit.

Without magnesium, our muscles would be in a constant state of contraction.

Magnesium is a required element of muscle relaxation, and without it our muscles would be in a constant state of contraction. Calcium, on the other hand, signals muscles to contract. As noted in the book The Magnesium Factor, the two minerals are “two sides of a physiological coin; they have actions that oppose one another, yet they function as a team.”8

Chvostek’s Sign and Trousseau’s Sign are both clinical tests for involuntary muscle movements, and both may indicate either calcium or magnesium deficiency, or both. In fact, magnesium deficiency may actually appear as calcium deficiency in testing, and one of the first recommendations upon receiving low calcium test results is magnesium supplementation.

Read more:

For a complete list of the conditions associated with magnesium deficiency, read our article,Symptoms of Low Magnesium.

To learn more about the role of magnesium in muscle function, see How Magnesium Functions in the Body.

10. Did you answer yes to any of the above questions and are also age 55 or older?

Older adults are particularly vulnerable to low magnesium status. It has been shown that aging, stress and disease all contribute to increasing magnesium needs, yet most older adults actually take in less magnesium from food sources than when they were younger.

In addition, magnesium metabolism may be less efficient as we grow older, as changes the GI tract and kidneys contribute to older adults absorbing less and retaining less magnesium.15

If you are above 55 and also showing lifestyle signs or symptoms related to low magnesium, it’s particularly important that you work to improve your magnesium intake. When body stores of magnesium run low, risks of overt hypomagnesaemia (magnesium deficiency) increase significantly.

Magnesium’s impact is so crucial and far reaching that symptoms of its absence reverberate throughout the body’s systems. This makes signs of its absence hard to pin down with absolute precision, even for cutting edge researchers.  Doctors Pilar Aranda and Elena Planells noted this difficulty in their report at the International Magnesium Symposium of 2007:

The clinical manifestations of magnesium deficiency are difficult to define because depletion of this cation is associated with considerable abnormalities in the metabolism of many elements and enzymes. If prolonged, insufficient magnesium intake may be responsible for symptoms attributed to other causes, or whose causes are unknown.”

Among researchers, magnesium deficiency is known as the silent epidemic of our times, and it is widely acknowledged that definitive testing for deficiency remains elusive. Judy Driskell, Professor, Nutrition and Health Sciences at the University of Nebraska, refers to this “invisible deficiency” as chronic latent magnesium deficiency, and explains:

Normal serum and plasma magnesium concentrations have been found in individuals with low magnesium in [red blood cells] and tissues. Yet efforts to find an indicator of subclinical magnesium status have not yielded a cost-effective one that has been well validated.”16

Yet while the identification of magnesium deficiency may be unclear, its importance is undeniable.

Magnesium activates over 300 enzyme reactions in the body, translating to thousands of biochemical reactions happening on a constant basis daily. Magnesium is crucial to nerve transmission, muscle contraction, blood coagulation, energy production, nutrient metabolism and bone and cell formation.

Considering these varied and all-encompassing effects, not to mention the cascading effect magnesium levels have on other important minerals such as calcium and potassium, one thing is clear – long term low magnesium intake is something to be avoided.

The Magnesium Miracle, by Carolyn Dean, M.D. N.D.

The longer your intake remains low, the more likelihood your bodily stores will be diminished, leaving you exposed to some of the more troubling side effects of long term deficiency. According to Dr. Carolyn Dean, M.D., N.D., and expert on magnesium therapy, adequate magnesium can improve heart health, prevent stroke and obesity, and improve mood and memory.

If you answered no to all of the above questions, you may be able to rely on high food sources of magnesium, like those described in our article onMagnesium in the Diet.

Yet for many people, especially those with diseases and symptoms associated with low magnesium, active magnesium supplementation may be a crucial element of returning to good health.

In her book, The Magnesium Miracle, Dr. Dean notes that achieving adequate magnesium through foods is notoriously difficult, stating:

I’m convinced that to get enough magnesium today, you need to take supplements.”4

Transdermal magnesium does not have the side effects of oral supplements.

One of the most effective ways to improve your magnesium levels is to combine a healthy diet with transdermal magnesium.

Many of the factors which contribute to low magnesiumstores are caused by inefficiencies of the GI tract. By delivering magnesium through the skin directly to the cells,topical magnesium products bypass many of the problems associated with low magnesium absorption.

In older adults, reduced gastric acid levels in the digestive system may be a factor in reduced mineral availability. Hydrochloric acid supplements may be combined with magnesium to combat this dilemma; however a simpler and less expensive option is the use of magnesium chloride supplements. Magnesium chloride has been proven to have a high bioavailability, while simultaneously providing the chloride necessary for healthy digestion and vitamin and mineral absorption.

Magnesium researcher Mildred Seelig has called magnesium “the silent guardian of our hearts and arteries” and “necessary for life”. And Dr. Carolyn Dean calls it “the missing link to total health”.

If you haven’t heard much about magnesium and its importance to good health, now is the time to learn. And if it’s something you’ve always meant to look into, now is the time to take action!

Mohammed, micronizing a drug does no increase its solubility. It only increase it dissolution kinetic (cd Noyes and Whitney equation). Solubility is only enhance when the size gets lower than 100 nm which is quite hard to get.

A simple method to improve the solubility is to form the amorphous form or use lipid-based formulations. I guess that lipid based formulation would bring you a wide latitude to find out the right composition (cf articles from Pouton, Charman and Porter from Monash university).

Dear Srimanta,

Critical process parameter (CPP): A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled

to ensure the process produces the desired quality – ICH Q8(R1)

Key process parameter (KPP): An adjustable process parameter (variable) of the process that, when maintained within a narrow range, ensures optimum process performance. A key process parameter does not meaningfully affect critical product quality attributes. Ranges for KPPs are established during process development, and changes to operating ranges will be managed within the Quality System – aMab

Hoping this will be helpful,

Rafik

links provides GLP; may be useful

In the sample prep, convert all gluconolactone into gluconic acid and You may be able to quantify as gluconic acid  by  HPLC using columns suitable for organic acids. ( some are with Ion exchange column and some with RP HPLC columns).

If you would like to quantify gluconolactone and gluconic acid simultaneously, you may need to use an alcohol and acetonitrile mixture as mobile phase and silica column. Use alcohol to prepare the sample.

Alternatively you may need to try silylation and quantify by Gas chropatography

Another think you can do is to adsorb both drugs in a third component such as colloidal silicon dioxide dispersed into wáter with the hydrophilic drug. Both drugs will adsorb onto silicon dioxide after evaporation of the organic solvent and can be managed as a unique component. I don´t know if that is useful to you. Best regards.

if needed you can use a sinker, but that phenomenon not affects on drug release. you also review again your dissolution medium

The most frequently used superoxide generation system in in vitro (cell free) assays is the use of xanthine (substrate) / xanthine oxidase (enzyme) as a reaction pair. 

According to literature, the amount of superoxide generated is roughly 1/3 of the xanthine amount added. 

See these two references: 

J. Am. Chem. Soc., 2013, 135 (40), pp 14956–14959

DOI: 10.1021/ja408524j

J. Am. Chem. Soc., 2015, 137 (21), pp 6837–6843

DOI: 10.1021/jacs.5b01881

Superoxide is thought to have very short half-life (in sub-second range, and said to be inversely correlated to its concentration). So, don't expect to see 100 uM superoxide to be there even if you use 300 uM xanthine (be careful that this substance has solubility limits). In fact, because of the high efficiency of superoxide dismutases and other endogenous enzymatic antioxidants in cells, cellular superoxide concentrations probably never reach uM range in equilibrium. 

You can get xanthine and xanthine oxidase from Sigma. 

See for reference a commercial kit here: https://www.caymanchem.com/pdfs/706002.pdf

 ***

As for  the scavengers, as a control, no undisputable scavengers can replace superoxide dismutases (SODs). You can buy SOD from Sigma. There is a cell-permeable form called PEG-SOD, available at higher prices. 

The acceptable chemical scavenger is 4-hydroxy-TEMPO (TEMPOL), though some studies used TEMPO (which exhibits unexpectedly more toxicity than TEMPOL). 

***

If you are interested in endogenously formed superoxide, try mouse macrophages, and stimulate them with PMA (phorbol ester) or LPS plus interferon-gamma. 

See this paper:

J. Am. Chem. Soc., 2015, 137 (21), pp 6837–6843

DOI: 10.1021/jacs.5b01881

Good luck. 

Dear Jitendra Bhangale,

You mean to develop fast dissolving dosage form of a drug; which is presently given by IV route...Why not? But what's the rationale behind this? As fast dissolving tablets are meant for oral administration; make sure drug's stability through oral route and its performance...And as mentioned by others, you can use super disintegrants for this purpose...But focus on rationale.

In tablets of identical composition, the less-porous type (higher compression force or longer dwell time, etc.) may dissolve more slowly. Intrusion of bulk solvent, possible through the pores, wets an outer layer and allows a tablet to disintegrate faster under most dissolution conditions than the "intrinsic dissolution rate" (a term normally reserved for a pure substance!) of a "dense" tablet surface. If your tablet contains disintegrants, the rates will be faster; if the tablet matrix is generally hydrophobic, the rates will be slower. You can visualize such solvent intrusion either (inexpensively) by coloring it (or incorporating a reagent which will generate a colored product with a tablet ingredient, e.g. iodine (as triiodide) + starch) and examining trial tablets destructively by abrading them on wet-dry type sandpaper series (coarse, then fine), or (expensively) non-destructively by 1H-MRI for water (typically). You might coat tablets for other reasons than to slow their dissolution; note that rupture-type coatings may give a sloppier release profile precision than will slowly-dissolving type coatings.

Sir i can suggest a formulation when if you tell me what type of extract is it, means ethanolic, ether, water etc, whether hydrophilic or hydrophobic. Secondly you want to develop formulation for crude extract or specific isolated compound from that extract??How much percent formulation you intend to prepare?? After knowing this, i can then help in formulation. If wana discuss in private, email at naumanpharma@gmail.com

The attached patent may be useful 

Dear Abhishek;

Bed temperature is not an independent  parameter it depends on inlet temperature and spray rate  so we can not fix the same bed temperature for all products.Their are so many factors which decides inlet temperature and spray rate like;

1.Coating system: Aqueous/Non aqueous.

2.Hardness of tablet and nature of drug product.

3.Size and surface ( score or embossed ) of Tablet

4.Occupancy in Pan etc.

Yes this exercise we did at drying stage where RH we control ..

Initially keep the drying temp as low as possible with high fuidization .....

Dissolve sodium hydroxide pellets in water , then add telmisartan slowly into it with continuous stirring to get clear solution.(solution 1)

Dissolve povidone with continuous stirring in purified water,, then add meglumine into it with stirring to get clear solution.(solution 2).

Mix step solution 1 and 2 with stirring.This solution is used as a spraying solution for top spray method in FBP on sorbitol /mannitol.

Lubricate the granules obtained by above process and compress in tablets.

I hope it will help you to obtain the desired  % drug release.

It could have practical use to construct multilayer tablet requiring the immediate and extended release of the same API. The immediate layer would release quickly to achieve the loading dose, while the secondary layer helps to keep up the constant dosage for the extended period of time. Doing that way, the dosage frequency could be brought down and constant drug blood concentration i.e drug within the therapeutic window will be maintained.  Requiring frequent drug intake would not have consistency in maintaining plasma drug level as the drug is always eliminating at the same time. So, administration of drug again have to go through the absorption process from all over again, which require some time before it show up any biological response. But, this problem could be greatly minimized by formulating it with the  extended release layer. Furthermore, complexing the drug with suitable polymers to make it follow zero kinetics would be really instrumental for the optimum alleviation of any symptoms. Specifically, it can be great boon in case of drugs with a short half-life, the potent  drug where plasma concentration typically fluctuates, which could lead to over or under medication and can encounter the condition where, it rise or fall beyond its therapeutic range. 

Sorbitol is also a common and good one

Hi! Esen,

Thanks a lot for your information. I've not used lactose in my formulation. The sitagliptin layer in my formulation contains MCC, DCP anhydrous, Crospovidone, PVP K30, Iron oxide yellow, SLS, SSF, Aerosil and water. I've done wet granulation for these tablets. 

Dear Peter Kapusta!

Thanks for your interest in my question. From the literature, I've known that BHT is widely used in production of LDPE bottle as antioxidant.  I specially run the spectrum of ethanol solution of pure BHT, and  observed the characteristic peak at 204 nm, consequently, it's asumed as the characteristic peak of BHT. How about your opinion? Looking forward to hearing from you.

Best regards!

Hi Abhishek,

I would suggest to change the phosphate. We did some experiments in the past and found out that amlodipine degradation is faster in presence of phosphate. Try carbonate and you will improve the stability of your formulation.

Regards

Wet granulation: PovidoneK 30 solution in water pr ethanol can be used to granulate hydrophobic drug powder, In that case longer mixing time me be needed.

Dry granulation: Mix PovidoneK 30 with drug and granulate by slugging method.

Safe, if no perforated eardrum. The vinegar and boric acid are used to *treat* mild swimmer's ear, by providing a hostile chemical environment to bacteria. The alcohol is used to help dry the external ear to *prevent* swimmer's ear. But, you don't indicate what you're trying to treat -- ear mites? If so, formic acid (in an appropriate vehicle) might be a better choice; it's a stronger acid, and used to treat mite infections in honeybee hives; -- severe swimmer's ear, or with eardrum perforation? If so, local antibiotics are effective; -- ear wax? If so, an oily humectant can soften, or a foaming (peroxide) agent, with expert irrigation in severe cases. Lots of literature out there --.

"The surfactant packing factor is expressed as v/(a*l), where "v" is the volume

of the surfactant tail, "a" is the surfactant area per molecule, and "l" is the length of the surfactant hydrophobe."

Enhancing Solubilization in Microemulsions—State of the Art and Current Trends, Jean-Louis Salager, Raquel E. Antón, David A. Sabatini*, Jeffrey H. Harwell, Edgar J. Acosta, and Laura I. Tolosa

Journal of Surfactants and Detergents

Methods in pharmacopoeia need validation..

Follow this article:

If you have any question, do not hesitate to ask.

If API has been co-dissolved in binder polymer solution then chances of aggregation is less, but there may be stability issue due to high energy amorphous state. If the drug is been dissolved in organic solvent and mixed with crystalline substance such as lactose then defenitely the API molecule is free to move and they can form larger crystals on evaporation of granulating solvent

For answers to a somewhat related question earlier posed at this forum, also dealing with gelatin coating: «Can anyone suggest a method to coat surgical grade titanium with a gelatin based film?» ─ you may check: https://www.researchgate.net/post/Can_anyone_suggest_a_method_to_coat_surgical_grade_titanium_with_a_gelatin_based_film

I do not know if I have understand the question correctly, but if you are going to dissolve your drug it does not matter if it is amorphous or crystalline. You usually talk about the solid state characteristics of the resulting nanosuspension that depend on manufacturing process; amorphous nanosuspension usually is the result of quenching method from an antisolvent, and crystalline nanosuspension resulting from wet bead milling (if you start with crystalline material).

Hi Sudip. The answer is quite long and complicated and nevertheless not too exhaustive. 

In short, the mechanism of action of the drug itself doesn't change. At best, in case the drug you are considering has more than one mechanism of action, you may redirect your formulation and favour one instead of the other.

However, what you ask in the title is not what you ask in the main message, and for that we need to be a bit more verbose. One of the challenge in drug delivery is having the maximum dose and the minimum side effects, which corresponds to the famous "magic bullet". In the design of drug delivery systems, for this reason, you try to use passive and active targeting strategies which should lead to a high concentration of the drug in the tissue/district of interest and lower (hopefully sub-effective) concentrations everywhere else. So, the drug itself does not become more potent BUT the therapeutic index is higher.

Then, again, you may want to consider what happens inside a single cell, and here the story gets out of control. One of the greatest problems we are still facing is the "effective" delivery. In other words, having a drug inside a cell doesn't mean the the drug will work. And I would use the word therapeutics here, rather than drug. You always have to hope, for example, to have endosomal escape and cytosolic release of the therapeutics. Or you have to circumvent the presence of transporters that can pump out your drug (or even your particles, sometimes) and in facts render the delivery absolutely ineffective. You may want to think of targeting specific organelles in the cells, like mitochondria. And once again, it is the combination of all these factors that render the drug "more potent".

Hello!

As per the established scientific literature proliposomes were one of those delivery systems which has proven to over come pre-systemic or first pass metabolism by enhancing lymphatic transport. However, practical evidence has to furnished for better understanding of this concept.  Proliposomes offer good potentiality for those drugs with low solubility and/or permeability limitations.

for your reference and proceeding further, here i attach my work (published)

Polysorbate 80 is undergoes degradation over time both in bulk as well as in aqueous solutions by two mechanisms a) auto-oxidation, cleavage at the ethylene oxide subunits; b) hydrolysis of the fatty acid ester bond.

Polyoxyethylene chains are susceptible, in presence of  oxygen over time, to oxidation of C-H groups to C-O-O-H (hydroperoxy) groups. The generation of peroxides and hydroperoxides from the auto-oxidative degradation of the polysorbate surfactants appears to result from reactive radical formation at both the polyoxyethylene and the olefin sites within the molecules. The hydroperoxy groups are susceptible to further degradation which leading to cleavage of the polyoxyethylene chains and, at least in a particular situations, formation of carbonyl compounds such as formaldehyde and acetaldehyde  which is further degraded to formic acid and/or other compounds as degradation products with a concomitant lowering of pH. Increased degradation leads to larger amounts of low molecular weight acids and, thus, a lower pH.

Oxidative degradation can also affect formulation ingredients other than those comprising polyoxyethylene chains, with a variety of undesirable effects, including, in addition to decline in physical stability and pH drift, Accumulation of degradation products that can be toxic or otherwise deleterious if administered by injection, and, where the ingredient subject to oxidative degradation is an active ingredient, loss of potency.

In aqueous formulations polysorbates can also hydrolyze with an apparent half-life of five months at 40°C. So due to hydrolysis of polysorbate 80, resulting degraded product may causes yellow coloration.

Higher Temperature may accelerated auto-oxidation and hydrolysis of polysorbate 80 and thus incease in degradation products.

Studies of polysorbate 80 at 80 ^oC showed that the reaction was catalyzed markedly below pH 3 and above pH 7.6. The lowest rates were obtained between pH 3–7.6 being essentially constant within that range. 

Light also increases the rate of polysorbate degradation in solution.

The resulting degradation product may be responsible for yellow coloration of final solution after heating at 120 C.

Storing the polysorbate solutions away from light, in the presence of nitrogen, pH between 3-7.6 most probably 5-7  and at lower temperatures helps prevent degradation from occurring and color change.

There is a simple chapter in Fanum's book on microemulsions, written by me and Pat Aikens, which gives you an overview on the phases involved in microemulsions.

If you need more information, my email is stic30kan@gmail.com 

you adapt any method..but you must keep track of the intended activity and also toxicity if you wish to apply any chemical methods. You can try enriching your extract by 1-2 column chromatographies. this will remove colour.

My question is basically knowing about the degradation of citric acid. there is no charring...and the solution thus obtained is giving a foul smell with blackish appearance.

On FT-IR spectra, some changes can be seen on peaks positions and peaks shapes. Some changes are related to bonding between API and excipients but some others can be due to a change in physical state; for example, the API can be crystalline before formulation (in that case, the IR peaks related to API are relatively sharper) but the formulation can induce some changes in the form of the API toward a more amorphous form (broader IR peaks); the same for some of the excipients. I would recommend to run IR spectra with the best resolution! (Worth keeping in mind that any physical stress on the samples may in some cases induce some physical changes too).

Hi , when particles are large they are not your supposed carrier they are just phospholipids(in the case of liposomes) that are accumulate .for making your carrier, penetration of medium to this bulk is necessary. By freezing you make your aqueous medium to crystallize and you know water in the form of ice will take more space than fluid so when you thaw it after that there will be more free space and voids .it helps the buffer to penetrate to the structure and make assembly easier .

Dear Raquel, just to say that if you go with using fresh (unfrozen) porcine skin, it may also be important to use skin that has not been steam-cleaned, since steam-cleaning can "cook" the skin and remove the stratum corneum in the process.