Molecular ProductCHEMICAL PRODUCT ENGINEERING ASEP MUHAMAD SAMSUDIN

Chemical Products

Commodities Chemical Devices Molecular Products

Microstructures Products

Examples Ethylene, ammonia Artificial kidneys Penicillin Sunscreen

Scale Continuum Meters Nanometers Micrometers

Key Cost Convenience Discovery Function

Basis Reaction Engineering, Unit operations

Reaction Engineering, Unit operations

Chemistry Recipe

Risk Feedstock Intellectual Property Discovery Science

Cussler and Moggridge

Cussler EL, Moggridge GD. Chemical product design. 2nd edition. Cambridge: Cambridge University Press; 2011.

Based on the characteristic size scale which is critical to their performance

Chemical ProductsCategory of

ProductClass of Product Example Key Attribute

Specialty chemicals

Surfactant Ammonium lauryl sulfate

Molecular structure

Formulated products

Cosmetic Exfoliating gel Microstructure

Bio-based concepts Drug Alendronate sodium

Biological activity

Devices Biomedical device Blood oxygenator Materials and assembly

Virtual chemical products

Software to simulate chemical processes

Aspen Plus Computational performance

Technology-based consumer goods

Health care consumer goods

Disposable diaper Materials and assembly

R. Costa and G. D. Moggridge

R. Costa, G. D. Moggridge, P. M. Saraiva. Chemical Product Engineering: An Emerging Paradigm Within Chemical Engineering. AIChE Journal, 52 (2006) :1979

Critical size of Chemical Products

Introduction

Molecular products are exemplified by pharmaceuti cals.

These products, which sell for much more than the cost of their ingredients, are sold to perform a particular task, like curing a disease.

Molecular products depend on two keys: their discovery and their time to market.

Drug discovery is remarkably inefficient. In justifying the high prices for drugs, company executives sometimes assert that it takes 10,000 candidates to find one successful drug.

Introduction

Drug development begin by identifying the target disease, and if possible, what we wish to manipulate (e.g. a particular protein).

We then spend perhaps four years and over half a billion dollars seeking drugs which influence this disease. This huge. expensive, inefficient search is where so many compounds are identified, synthesized, and abandoned.

At the end of this saga, we begin animal testing, where our success rate is only about 10%. The animal testing will normally involve a sequence of mice. rats, and dogs.

At the end of this ordeal, we will have identified a possible target molecule. This is the point where engineering starts to become involved.

Introduction

This engineering involvement centers on the second key aspect of molecular products, the speed of their development or their time to market.

This is impor tant because the first molecular product to be sold for a specific task normally garners two thirds of the sales in this area.

In this engineering-based develop ment we will use the same design template of needs, ideas, selection, and man ufacture to bring the chemical product to market.

We will decide what amounts and purity of the target molecule are needed. We will generate ideas to make and purify this molecule, and we will use generic equipment to manufacture batches of our product.

Characteristic of Molecular Products

Molecular products are high-value molecules, such as pharmaceuticals.

These molecules usually have molec ular weights of 500 to 3000 daltons, though some antibodies can have molecu lar weights of several million.

These species are obtained in three different ways. Antibiotics, like penicillin are examples of molecules produced

by fermentation. Prozac (fluoxetine), an antidepressant, is an example made by

chemical synthesis. Products are mixtures of pharmaceutically active species

prepared by a specific process, often from a bio logical feedstock. e.g. Premarin

Characteristic of Molecular Products

Penicillin

Prozac

Premarin

Characteristic of Molecular Products

Molecular products are typically made in small quantities, often less than ten tons per year. They sell for high prices, often over $100/kg.

One good example is Zoladex (goserelin acetate), a decapeptide used to treat both breast and prostate cancers.

Forty-six kilograms of the drug is made each year, selling for $800 million. Compounds like this are not synthesized in opti mized. dedicated equipment, but are made periodically in generic equipment.

The Rule of Five

Suggested by C. A. Lipinski of Pfizer. This rule, which does not apply to natural products, estimates the chance

of clinical success for a drug to be administered orally. It suggests that drugs must meet four criteria:

1. The drug must have five or fewer hydrogen-based donors. This is the sum of -OH and -NH groups.

2. The drug must have fewer than ten hydrogen-based acceptors. This is the sum of the molecule's nitrogen and oxygen atoms.

3. The drug's molecular weight must be under 500. This does not include species like HC1 or NaOH added to enhance solubility.

4. The logarithm of the drug's partition coefficient Kow between octanol and water must be less than five. In other words, its octanol solubility must be less than 100.000 times its water solubility.

The first and second rules describe the drug's chemistry; the third is a mea sure of size; and the fourth suggests that to reach human tissue, the drug must pass through water.

The Rule of Five

Clinical Trials

Phase I is a small study of around twenty healthy, paid volunteers. The study accesses the molecular product's toxicity and pharmacokinetics, usually in an outpa tient clinic.

Phase II typically with 50 volunteers, some of whom have the target disease. Phase II includes studies of how much drug should be given and how well the drug works. Phase II is the step where most drugs fail, often because side effects are too serious.

Phase III, involving perhaps 1000 patients at several different locations, aims to collect statistically significant data for final submission, seeking approval for the drug from the FDA. These trials are tedious, averaging eight years for a new drug. They are a major reason why drugs are expensive,

Molecular Product Design

We will develop the process for such a product using our normal design sequence of "needs," "ideas," "selection," and "manufacture."

The "needs" step is easy: it is just the amount and purity of the target molecule to be made fast to meet the demands of the clinical trial. Needs may also include secondary con straints, such as discharge streams and available raw materials.

The "ideas" step is a several of possible processes drawn from laboratory experiments and pub lished patents. Each process idea will include inventing a reaction-path sequence and separation processes.

The "selection" step is the hard one because we will need to simplify our process ideas quickly, and we will not have time to do the obvious but tedious experiments which would assure our success.

The "manufacturing" step will again be easy because its scale isn't so different to the bench process. Thus we need to work on the "ideas" and "selection" steps.

Synthesis of material flow for Molecular vs. Commodity Products

Decisions Molecular product Commodity product

Process type Batch ContinuousReactions Often complete; few recycles Partial; requires recycles Separations Extraction, precipitation,

chromatography, crystallizationDistillation, gas absorption

The sequence of decisions is the same, but the alternatives chosen are different.

Reaction-Path Synthesis

Once the target molecule is identified, the synthetic chemists on the team will start to think of possible routes for the synthesis.

Going backwards from the target molecule to simple precursors. called "the disconnection approach," is common.

This approach, outlined by Warren and Wyatt (2009). makes succes sive "disconnections" to reduce the target molecule to simple, available precur sors.

Each disconnection involves imagining breaking the structure of the target molecule: this breakage is the reverse of a synthetic step.

Usually, several different disconnections are possible for any target molecule. Thus, many alternative synthetic routes can easily be deduced.

Sometimes. none of the potential routes will look viable. Alternativelv, it might be extracted from a natural product or made via fermentation.

Reaction-Path Synthesis

Phenoglycodol Synthesis

Separation Synthesis

1. Concentrate the product before purification.2. Remove the most plentiful products early.3. Do the hardest separation last4. Remove any hazardous materials early.5. Avoid adding new species during the separation, If

they must be added, remove them promptly.6. Avoid extreme temperatures by using different

solvents.

General Rules

Separation Synthesis

1. Removal of insolubles. The fermentation broth or other natural feedstock is filtered.

2. Isolation. The product in the filtrate or the cake is isolated, that is con centrated. often by extraction.

3. Purification. The concentrate is partially purified, most often by chro matography.

4. Polishing. The purified product is purified again, most often by crystallization.

Fermentation Rules

Amylase Purification using RIPP sequence