Center of Excellence for Aging & Brain Repair

CNS D³ Laboratory


There are three early stages of drug discovery and development (D³). Stage one of D3 begins with the discovery of a specific molecule, a lead active pharmaceutical ingredient (API). Once a molecule with promising biological activity has been identified a second stage (preformulation) identifies a solid form of the molecule that has optimal physicochemical properties. This material is called a drug substance or API. When an API is combined with other materials (e.g. excipients), it enters the third stage of D3 (formulation). The drug product that is most commonly produced is in the form of an oral tablet.

Our laboratory primarily focuses on central nervous system (CNS) D³. Our research strategy often involves naturally derived compounds with therapeutic potential for various neuropsychiatric disorders. Once a lead API is identified, we optimize its therapeutic efficacy using preformulation and formulation interventions. Our preformulation strategy employs crystal engineering techniques to generate novel crystal forms with improved physicochemical properties. These optimal physicochemical properties often lead to improvements in therapeutic efficacy. If the preformulation screens fail to yield the desired improvements in efficacy of a lead API, we apply formulation strategies such as nanocarrier systems.

Key Capabilities

  • Pharmacokinetics (preclinical and clinical)
  • Pharmacokinetics modeling (Phoenix WinNonlin™)
  • Solid form screening (e.g. polymorphs, solvates, salts, cocrystals)
  • Physicochemical characterization (e.g. IR-spectroscopy, powder x-ray diffraction, single crystal x-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, nuclear magnetic resonance)
  • Efficacy
  • Toxicity


We welcome collaborative pursuits and/or contract research. For more information please contact Dr. Adam Smith.

Selected Publications

Smith AJ, Kim SH, Duggirala NK, Jin J, Wojtas L, Ehrhart J, Giunta B, Tan J, Zaworotko MJ, Shytle RD (2013). Improving Lithium Therapeutics by Crystal Engineering of Novel Ionic Cocrystals. Mol Pharm Doi: 10.1021/mp400571a.

Smith AJ, Kavuru P, Arora KK, Kesani S, Tan J, Zaworotko MJ, & Shytle RD (2013). Crystal engineering of green tea epigallocatechin-3-gallate (EGCg) cocrystals and pharmacokinetic modulation in rats. Mol Pharm doi: 10.1021/mp4000794.

Smith AJ, Kavuru P, Wojtas L, Zaworotko MJ, Shytle RD (2011). Cocrystals of quercetin with improved solubility and oral bioavailability. Mol Pharm 8(5): 1867-1876.

Smith AJ, Giunta B, Shytle RD, Blum JM. (2011). Evaluation of a novel supplement to reduce blood glucose through the use for a modified oral glucose tolerance test. Am J Transl Res, 3(2):219-225.

Smith AJ, Giunta B, Bickford PC, Fountain M, Tan J, Shytle RD (2010). Nanolipidic particles improve the bioavailability and alpha-secretase inducing ability of epigallocatechin-3-gallate (EGCg) for the treatment of Alzheimer's disease. Int J Pharm 389(1-2): 207-212.

Sanberg PR, Vindrola-Padros C, Shytle RD. Translating laboratory discovery to the clinic: From nicotine and mecamylamine to Tourette’s, depression, and beyond. Physiology & Behavior, 2012

Shytle RD, Penny E, Goldman J, Sanberg P (2002) Mecamylamine (Inversine®): An Old Antihypertensive Medication with New Research Directions? Journal of Human Hypertension 16:453-457.

Bacher I, Wu B, Shytle RD, George TP. (2009) Mecamylamine - a nicotinic acetylcholine receptor antagonist with potential for the treatment of neuropsychiatric disorders. Expert Opin Pharmacother. 10(16):2709-21.

Shytle RD, Silver AA, Wilkinson BJ, Sanberg, PR (2002) A Pilot Controlled Trial of Transdermal Nicotine in the Treatment of Attention Deficit Hyperactivity Disorder. World Journal of Biological Psychiatry 3:150-155.

Newman MB, Manresa JJ, Sanberg PR & Shytle RD (2001) Effects of Low Doses of Mecamylamine in Two Animal Models of Anxiety.Experimental and Clinical Psychopharmacology 10(1):18-25.

Shytle RD, Silver AA, Sanberg, PR (2001) Mecamylamine for Smoking Cessation. Internal Medicine News. 34(19):5.

Newman MB, Manresa JJ, Potts SE, Alvarez F, Sanberg PR & Shytle RD (2001) Nicotine Induced Seizures Blocked By ()-Mecamylamine And Its Stereoisomers. Life Science 69:2583-2591.

Silver AA, Shytle RD, Sheehan D, Sheehan K, Ramos A, & Sanberg PR (2001) Multi-Center Double Blind Placebo Controlled Study of Mecamylamine Monotherapy for Tourette Disorder. Journal of the American Academy of Child and Adolescent Psychiatry 40(9): 1101-1110.

Young J, Shytle RD, Sanberg PR, George T (2001) Mecamylamine (Inversine®): New Therapeutic Uses and Toxicity/Risk Profile Clinical Therapeutics 23(4): 532-565.

Papke R, Sanberg PR, & Shytle RD (2000) Analysis on Mecamylamine Stereoisomers on Human Nicotinic Receptor Subtypes. Journal of Experimental Pharmacology and Therapeutics 297(2): 646-656.

Silver AA, Shytle RD, & Sanberg PR (2000) Mecamylamine in Tourette’s Syndrome: A two year retrospective case study. Journal of Child and Adolescent Psychopharmacology 10:59-68.

Shytle RD, Silver A, & Sanberg PR (2000) Comorbid Bipolar Disorder in Tourette Syndrome Responds to Nicotinic Receptor Antagonist, Mecamylamine (Inversine®). Biological Psychiatry 48:1028-1031.

Sanberg PR, Silver AA, & Shytle RD (1998) Treatment of Tourette’s Syndrome with Mecamylamine. Lancet 352:705-706.

Sanberg PR, Silver AA, Shytle RD, Philipp MK, Cahill DW, Fogelson HM, McConville BJ (1997). Nicotine for the Treatment of Tourette’s Syndrome. Pharmacology and Therapeutics 74(1): 21-25.

Shytle RD, Silver AA, Philipp MK, McConville BJ, Sanberg PR (1996). Transdermal Nicotine for Tourette’s Syndrome. Drug Development Research 38(3/4): 290-298.